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J Appl Physiol 91: 1421-1430, 2001;
8750-7587/01 $5.00
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Vol. 91, Issue 3, 1421-1430, September 2001

HIGHLIGHTED TOPICS
Signal Transduction in Smooth Muscle
Invited Review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression

Thomas M. Lincoln, Nupur Dey, and Hassan Sellak

Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MECHANISMS OF SMOOTH MUSCLE...
REGULATION OF VSMC PHENOTYPE
CONCLUSIONS
REFERENCES

cGMP is a second messenger that produces its effects by interacting with intracellular receptor proteins. In smooth muscle cells, one of the major receptors for cGMP is the serine/threonine protein kinase, cGMP-dependent protein kinase (PKG). PKG has been shown to catalyze the phosphorylation of a number of physiologically relevant proteins whose function it is to regulate the contractile activity of the smooth muscle cell. These include proteins that regulate free intracellular calcium levels, the cytoskeleton, and the phosphorylation state of the regulatory light chain of smooth muscle myosin. Other studies have shown that vascular smooth muscle cells (VSMCs) that are cultured in vitro may cease to express PKG and will, coincidentally, acquire a noncontractile, synthetic phenotype. The restoration of PKG expression to the synthetic phenotype VSMC results in the cells acquiring a more contractile phenotype. These more recent studies suggest that PKG controls VSMC gene expression that, in turn, regulates phenotypic modulation of the cells. Therefore, the regulation of PKG gene expression appears to be linked to phenotypic modulation of VSMC. Because several vascular disorders are related to the accumulation of synthetic, fibroproliferative VSMC in the vessel wall, it is likely that changes in the activity of the nitric oxide/cGMP/PKG pathway is involved the development of these diseases.

vascular smooth muscle cells; nitric oxide


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MECHANISMS OF SMOOTH MUSCLE...
REGULATION OF VSMC PHENOTYPE
CONCLUSIONS
REFERENCES

NITRIC OXIDE (NO) is an important regulator of vascular and nonvascular smooth muscle relaxation. The mechanism by which NO produces relaxation is the subject of much investigation. It is generally conceded that activation of soluble guanylyl cyclase is the principal intracellular event that initiates relaxation, but the events that occur downstream from cGMP formation are still much debated (see Refs. 29, 44, and 63 for    reviews). cGMP activates a family of serine/threonine protein kinases, the cGMP-dependent protein kinases (PKG), in smooth muscle cells, and it is likely that there are several different phosphorylation events occurring in response to PKG activation that lead to relaxation. A discussion of the enzymology and functions of the two types of PKG will not be dealt with here because they have been reviewed elsewhere (30, 65). Just how important the NO/cGMP/PKG pathway is in the regulation of smooth muscle tone may be surmised from studies on genetically altered mice lacking components of this pathway. Thus mice lacking endothelial NO synthase or PKG demonstrate moderate hypertension, indicative of increased vascular tone (45, 81).

More recently, another regulatory role for the NO/cGMP/PKG pathway has been proposed in vascular smooth muscle: the control of the vascular smooth muscle cell (VSMC) phenotype. This review will discuss studies that have shown that NO signaling inhibits VSMC proliferation in vitro and in vivo, although the mechanism and physiological significance are still not well understood. Others have shown that NO signaling, via a cGMP mechanism, regulates gene expression in cells. These effects have been extended to VSMCs where cGMP and PKG appear to regulate phenotypic properties of the cells. These later studies may have important implications for our understanding of vascular disorders such as atherosclerosis and restenosis.


    MECHANISMS OF SMOOTH MUSCLE RELAXATION
TOP
ABSTRACT
INTRODUCTION
MECHANISMS OF SMOOTH MUSCLE...
REGULATION OF VSMC PHENOTYPE
CONCLUSIONS
REFERENCES

There appear to be three major pathways regulated by NO/cGMP/PKG signaling that induce relaxation in smooth muscle: decreases in intracellular free calcium concentrations, calcium desensitization, and thin filament regulation. It is likely that no single pathway acts exclusively or independently in any one type of smooth muscle cell. However, the relative importance of the various pathways leading to cGMP-induced relaxation is likely to be different in phasic compared with tonic contractile cells and in cells from large arteries compared with those from microvessels.

Regulation of intracellular calcium. The first mechanism proposed for cGMP-dependent relaxation of smooth muscle was the reduction of free intracellular cytosolic calcium concentrations (49, 61). Insofar as increases in calcium were required for myosin light-chain (MLC) phosphorylation and contraction, the reduction of calcium by cGMP was seen primarily as a reversal of the contractile mechanism. Numerous studies over the past decade have supported a mechanism that involves the reduction of cytosolic calcium and the subsequent dephosphorylation of MLC. The earliest observations demonstrated that cGMP-dependent relaxation was observed for both agonist-dependent (e.g., alpha -adrenergic agonists) contraction and depolarization-dependent contraction. Because the former contractile mechanism utilizes a G-protein-coupled pathway to increase intracellular calcium, whereas the latter utilizes the activation of voltage-gated calcium channels to increase calcium, reductions in the rises in calcium to either of these pathways by cGMP-dependent mechanisms made "physiological sense."

Several sites of action have been proposed to account for cGMP-dependent regulation of cytosolic calcium, and these have been reviewed elsewhere (44, 63). These include sequestration and the removal of intracellular calcium through calcium pump mechanisms, inhibition of voltage-gated calcium channels, and inhibition of receptor/G-protein coupling in smooth muscle. However, two newer mechanisms have been reported in the past 2 years that deserve comment. The first of these is an increase in calcium-activated potassium channel gating that is activated by calcium, the so-called BK channels. Increased BK channel activity hyperpolarizes the membrane and reduces intracellular calcium influx through voltage-gated calcium channels. Increased BK channel activity appears to arise from both a direct activation of the channel by PKG and increased activity of spontaneous transient outward currents (STOCs) produced by small bursts of calcium released from the superficial sarcoplasmic reticulum (SR) that activate the channel (75). In the former case, it has been proposed that PKG regulates the phosphorylation of the BK channel either by acting as the direct catalyst for phosphorylation (1, 3, 31) or by activating a protein phosphatase that dephosphorylates the BK channel (111, 117). These results imply that there may be cell- and tissue-specific BK channels that are activated by PKG, one type activated by phosphorylation and the second type activated by dephosphorylation. In the case of increased STOC activity, it has been proposed that PKG increases influx of calcium into the superficial SR or activates a ryanodine receptor or both. The net effect would be a localized release of calcium from the SR into the subplasmalemmal space toward the plasma membrane to activate the BK channel (83). As a result of BK channel activation, a decrease in global intracellular calcium occurs, leading to the dephosphorylation of MLC and relaxation. The molecular mechanisms responsible for the PKG-dependent control of calcium flux into and out of the SR are not clear, although it is generally conceded that phosphorylation of the SR protein, phospholamban, by PKG contributes to SR calcium loading (24, 51, 66, 71, 89). In fact, phospholamban knockout mice have diminished STOC activity and decreased PKG-dependent activation of BK channels (110). A model depicting the PKG-dependent regulation of BK channel activity is shown in Fig. 1.


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  		Fig. 1.   Model for the activation of large-conductance Ca2+-activated K+ channels (BK channels) in smooth muscle by cGMP-dependent protein kinase (PKG). Two mechanisms are depicted for channel activation: direct phosphorylation of the channel and indirect activation of the channel by increasing the spontaneous outward transient currents (STOCs). Direct phosphorylation and PKG-dependent dephosphorylation of BK channels have both been proposed. For increasing the STOC activity, PKG activates the uptake of Ca2+ into the superficial sarcoplasmic reticulum (SR) by the phosphorylation of phospholamban (PLB) and activation of the SR Ca2+-ATPase (SERCA). Loading of Ca2+ in the SR provides greater Ca2+ for release into the submembrane space toward the plasma membrane (PL). Ca2+ then activates the BK channel. PKG also catalyzes the phosphorylation of the inositol trisphosphate receptor (IP3R) or the ryanodine receptor (RyR), which could result in enhanced release of localized Ca2+ into the submembrane space. Either or both effects activate BK channels, resulting in the hyperpolarization of the cell and a decrease in Ca2+ influx through L-type Ca2+ channels. The net effect of decreased Ca2+ influx would be a decrease in global cell Ca2+ and relaxation. PKG may also have direct effects to inhibit Ca2+ channel activity.

The other major development in the area of the control of intracellular calcium levels by cGMP/PKG is the regulation of the inositol 1,4,5-trisphosphate (IP3) receptor. Previous studies from several laboratories demonstrated that the smooth muscle type I IP3 receptor is phosphorylated by PKG (17, 43, 55-57, 72, 73). This protein was in fact initially termed the G0 protein substrate by Casnellie and Greengard (16). The result of phosphorylation of the IP3 receptor has not been clearly defined. The laboratory of Hofmann and Ruth and colleagues (91), however, showed that PKG-dependent phosphorylation of the IP3 receptor decreases calcium release from the SR, and this effect is dependent on the targeting of PKG to the SR. A targeting protein for PKG termed IRAG (IP3 receptor-associated PKG-I substrate) has been characterized and shown to be necessary for IP3 receptor phosphorylation.

Regulation of calcium sensitization. MLC phosphorylation at serine-19 is necessary for actin activation of myosin ATPase and subsequent cross-bridge cycling. Two key enzymes involved in the control of MLC phosphorylation are myosin light chain kinase (MLCK), a calcium/calmodulin-activated kinase, and MLC phosphatase, a serine/threonine protein phosphatase type I. With respect to regulation of MLCK, there has been no firm evidence that PKG-dependent phosphorylation of MLCK inhibits its activity (104). Most of the recent work suggests that PKG activates MLC phosphatase, thereby inhibiting MLC phosphorylation and contraction. The initial studies by Nishimura and van Breemen (76) and subsequently characterized by Lee et al. (60) and others (52) demonstrated that cGMP analogs inhibited agonist-induced calcium sensitization of contraction. Calcium sensitization is the term used to describe the increase in contractile activity produced by G-protein-coupled agonists compared with depolarization. Greater levels of contraction and MLC phosphorylation could be achieved at much lower levels of intracellular calcium using contractile agonists compared with potassium depolarization. An important component of the calcium sensitization mechanism is the Rho-Rho kinase-dependent inhibition of MLC phosphatase following agonist stimulation of contraction (35, 54). PKG apparently opposes Rho kinase-induced inhibition of the phosphatase by phosphorylating the myosin-binding subunit (MBS) of MLC phosphatase, thus activating the catalytic subunit of the phosphatase (100, 103). These studies have also shown that PKG is targeted to the MBS, thus placing it in an ideal location to activate MLC phosphatase. This scenario, similar to the one proposed for targeting of PKG to the IP3 receptor, relies on the localization of PKG to its substrates for the subsequent induction of relaxation. It is noteworthy that the specific PKG substrate, G1 protein [also described by Casnellie and Greengard (16)], is likely to be the MBS.

There are further reports that suggest that cGMP/PKG may interfere directly with the Rho-dependent activation of Rho kinase, possibly through the phosphorylation of Rho (90). Several studies have now shown that several of the small GTP binding proteins that converge on the contraction pathway in smooth muscle (e.g., Rho and Rap1) could be physiological substrates for PKG (69, 106). Finally, Wu et al. (114) showed that PKG-mediated desensitization of visceral smooth muscle may involve the phosphorylation of telokin. Clearly, the control of VSMC contraction through the regulation of MLC phosphorylation is an important target in NO/cGMP/PKG signaling.

Thin filament regulation. The role of the thin filament in the regulation of smooth muscle cell contraction has been somewhat controversial. Thin filament binding proteins regulate and contribute to the contractile activity of the cell, but there have been very few reports regarding the role of second messenger regulation of thin filament protein function. Two thin filament/actin binding proteins [vasodilatory-stimulated phosphoprotein (VASP) and the 20-kDa heat shock-related protein (HSP20)] have raised interest in possible regulation of smooth muscle cell contraction via thin filament regulation.

VASP was first identified and characterized by Walter and colleagues (13, 85) from platelets. VASP binds to actin filaments and stress fibers in practically all cells studied. It is particularly abundant in focal adhesions of cultured cells. Both cAMP-dependent protein kinase (PKA) and PKG catalyze the phosphorylation of VASP, resulting in a reduction in the number of focal adhesions (28, 74, 96). It has been reported that VASP phosphorylation on the PKG-specific site decreases the binding of VASP to actin filaments, possibly through its dissociation from the actin binding protein profilin (84). Although it is clear that VASP plays a critical role in cell spreading and movement, its role in smooth muscle contraction is less well defined.

More recently, HSP20 has gained some attention as a potential target for PKG action. Both HSP27 and HSP20 have been implicated in the regulation of smooth muscle contraction (6, 115). HSP20 was reported by Brophy and colleagues (5, 12) to be a specific target for both PKA- and PKG-dependent phosphorylation. Phosphorylation of serine-16 by either kinase is associated with relaxation of smooth muscle. Moreover, smooth muscle that does not relax in response to cyclic nucleotides (i.e., umbilical artery) does not demonstrate phosphorylation of HSP20. Studies using inhibitory peptides for HSP20 in both Brophy's and Rembold's laboratories (5, 12, 86) indicate that HSP20 mediates relaxation primarily through interactions with thin filaments. It is likely that this interesting system will be a major target for investigations of the NO/cGMP/PKG pathway in smooth muscle relaxation.


    REGULATION OF VSMC PHENOTYPE
TOP
ABSTRACT
INTRODUCTION
MECHANISMS OF SMOOTH MUSCLE...
REGULATION OF VSMC PHENOTYPE
CONCLUSIONS
REFERENCES

Whereas there is widespread acceptance of the important role for PKG in regulating smooth muscle cell contractility and vascular tone, a newer role for PKG in the regulation of VSMC phenotype is emerging that might prove to be just as important for vascular function. It is important to mention at the outset that it is not our intention here to review the huge volume of literature regarding VSMC phenotypic modulation and growth and the theories and controversies about the development of vascular lesions. Rather, it is our intention to focus on the emerging role of the NO/cGMP/PKG system in VSMC gene expression and how this may relate to vascular diseases.

With these caveats in mind, it has long been established that VSMCs acquire altered phenotypes in response to vessel growth, vascular injury, or even the in vitro culturing of VSMCs (15, 18, 19, 36, 70, 78). In contrast to the development of smooth muscle cells from relatively dedifferentiated precursor cells to mature, differentiated contractile cells, the modulation of mature VSMCs between contractile phenotypes and synthetic or secretory phenotypes is a response to injury of the vessel (67, 88). The modulation of VSMC phenotype is a complex process that involves not only cells present in the medial layer of the vessel wall but also myofibroblasts derived from the adventitial layers (112) and even circulating cells derived from the bone marrow (42). Each of these different cell types is capable of migrating into the intimal areas in response to injury. There, the cells proliferate and secrete new matrix proteins in the wound-healing response. To complicate matters further, the medial smooth muscle cells are themselves heterogeneous, some derived from different germ layers, with some existing in a more synthetic state and others maintaining a more contractile phenotype (21, 99).

Regardless of the origin of the intimal cells during the response to injury, it is well established that VSMCs, representing the major cell type present in the vessel wall, acquire the capacity to proliferate and synthesize extracellular matrix (ECM) proteins, hence the terms synthetic or secretory to describe this phenotype. The synthetic phenotype of the VSMC is also acquired during the in vitro culturing of the cells; therefore, cultured VSMCs have become an accepted model for examining mechanisms of phenotypic modulation. Because cells that modulate to the synthetic phenotype cease synthesizing contractile proteins and pharmacomechanical signaling molecules (ion channels for instance) to produce ECM proteins, there are predictably dramatic changes in gene expression in response to injury. Many of the changes in gene expression and pathways leading to such changes have been reviewed elsewhere (18, 78). The role of the NO/cGMP/PKG pathway in regulating smooth muscle gene expression, however, is a relatively newer concept in vascular biology.

Studies performed more than 10 years ago established a potentially important role for NO in the inhibition of VSMC proliferation in vitro and in vivo (33, 68). Recent studies suggest a role for NO in the regulation of the expression of cell cycle control proteins such as p21 (Waf1/Cip1) and p53 (37, 38, 53, 102). In many of these studies, the mediation of the effects of NO was linked to cGMP and PKG activation. In other studies, however, the effects of NO were found to be either independent of cGMP or at least independent of PKG activation. Although these studies suggest an important role for NO/cGMP signaling in regulation of VSMC cell cycle events, it is important to distinguish between the proliferation of VSMC on the one hand from the changes in the pattern of gene expression resulting in different proteins being made in the cells on the other. Both contractile cells and synthetic cells are capable of proliferation in vitro and in vivo (99). When injury and the liberation of growth factors during injury occur, there is an immediate proliferative response of contractile and synthetic cells that lasts for 7-14 days, depending on the species and type of injury. The proliferation of cells in the intima is accompanied by the migration of new smooth muscle cells into the intima. The new population of cells in the intima constitutes only a minor portion of the new mass of tissue that results from injury. The major contributing factor to the new mass of intimal tissue is the synthesis and secretion of ECM by intimal cells, a process that continues even after the proliferative response has subsided (99). The changes in gene expression and phenotype of VSMCs that permit the cells to acquire the capacity to synthesize new ECM and shut down production of contractile protein synthesis are processes that may be unrelated to the proliferative activity of the cell. Thus the process by which NO inhibits VSMC proliferation may be distinct from the processes by which NO regulates gene expression and phenotype of VSMC. Because most of the investigations on the role of NO in arterial response to injury have focused only on proliferation, the mechanisms by which NO signaling may change VSMC gene expression and phenotype are largely unknown.

Much of the early work on the mechanisms by which PKG regulates gene expression in cells were performed in cells other than VSMCs. Pilz, Boss, and colleagues (39, 40, 47, 82) have shown that PKG is a key regulator of protooncogene expression in cells such as BK cells transfected with the cDNA encoding the kinase. Studies in these and other cell types by other investigators have shown a similar potential for cGMP/PKG signaling in regulating specific mRNA transcription (8, 23, 32, 34, 41, 48, 58, 63, 80, 93, 107). The molecular mechanisms involving PKG-regulated transcription are not well understood, although it has been reported that activation of the cAMP response element, serum response element, and activator protein-1 elements by PKG is involved in the mechanism (34, 39, 40, 48, 93). In VSMCs, it is well established that specific promoter elements control the expression of contractile protein genes in development, and many of these promoter elements may be involved in gene expression in phenotypic modulation. A more thorough discussion of the transcriptional control for smooth muscle cell gene expression is beyond the scope of this review, and the reader is referred to a recent summary relating to smooth muscle cell-specific gene expression (79). Nevertheless, there are several common elements found in smooth muscle-specific promoters for contractile proteins, ECM proteins, and other smooth muscle-specific genes. At this time, however, there are no studies relating to the regulation of these promoters or the specific regulatory elements contained within these promoters by NO or PKG signaling. Findings that directly implicated a specific role for cGMP and PKG in the regulation of VSMC phenotype and gene expression were first reported by Boerth et al. (9, 10, 27, 62). In these studies, adult rat aortic VSMCs that were highly passaged and deficient in PKG expression were found to demonstrate increased production of smooth muscle myosin heavy chain, alpha -actin, and other markers of the contractile phenotype in response to the restoration of PKG expression. Likewise, inhibition of ECM protein production was also found to occur in response to restoration of PKG expression. In some cases, increased expression was found to be dependent on the increased steady-state production of the mRNA for these proteins, whereas, in others, the processing of mRNA may be regulated by cGMP-dependent protein phosphorylation (107). In the case of the decrease in matrix protein production, some level of posttranscriptional control appears to be present (27). In a preliminary report (20), PKG was found to regulate the expression of ~123 genes in cultured human VSMCs. Collectively, these studies indicate that the NO/cGMP/PKG signaling pathway has the capacity to control the expression of proteins in cultured VSMCs and that the expression of these proteins may regulate the morphology and the phenotype of the VSMC.

There are likely to be major regulatory differences in the development of VSMCs from mesenchymal stem cells on the one hand and the modulation of adult VSMCs between contractile and synthetic phenotypes on the other. As mentioned earlier, elegant studies by several laboratories have established important elements in the genes of smooth muscle-specific proteins that must be turned on during development. However, there is no evidence at present that the NO/cGMP/PKG pathway controls the program for smooth muscle cell development. In fact, PKG-deficient mice appear to have relatively normal vessel function, at least as juvenile animals; thus it is unlikely that PKG has a role in gene expression during development (81). On the other hand, the cGMP/PKG pathway may regulate phenotypic modulation of adult VSMCs between phenotypes. This may have some physiological relevance in that endothelial dysfunction or disruption following injury would decrease NO production and inhibit activation of the PKG pathway in the smooth muscle cells. It would be as a result of this type of injury that wound-healing activity of the cells would be important for vessel repair and function. The studies using cultured VSMCs suggest that PKG is at least one key factor regulating the establishment of a contractile-like phenotype.

If there are very few studies that implicate an involvement of the NO/cGMP/PKG pathway in the control of VSMC gene expression in vitro, there are fewer yet in vivo studies (2, 109). Anderson et al. (2) showed that, subsequent to balloon coronary artery injury in the swine, PKG expression is decreased within days after angioplasty and coincident with the loss of calponin expression, a marker protein for the contractile phenotype. As shown in Fig. 2, there was also a corresponding increase in time with the expression of osteopontin, a marker for the synthetic phenotype. It was interesting to note that only in the VSMCs that were undergoing proliferation and were presumably actively involved in wound-healing activity did PKG levels drop in the cells. These results suggest that the decreases in PKG expression may be causally related to the injury response of the VSMC. Therefore, these in vivo studies, coupled with the in vitro studies demonstrating dramatic effects of PKG on VSMC morphology and protein and gene expression, suggest that PKG occupies a central switch in the modulation of VSMC phenotype in response to injury.


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  		Fig. 2.   PKG expression in swine coronary artery 7 days after balloon catheter injury. A: hematoxylin and eosin (H&E)-stained section through the artery, demonstrating the newly formed neointima (arrows) at the shoulders of the repaired medial laceration. Ad, adventitia; M, media. B: higher magnification of an H&E-stained section through the coronary artery at the shoulder of the medial laceration (arrow) that has begun the repair process with the formation of a neointima (N). C: PKG staining of an adjacent section. D: bromodeoxyuridine staining of an adjacent section demonstrating proliferation of cells. E: osteopontin staining of an adjacent section for synthetic phenotype cells. F: calponin staining of an adjacent section for contractile phenotype. Arrowheads in B-F indicate the position of the external elastic lamina separating the media from the adventitial layer. Arrows in B-F indicate lesion site where active tissue repair is occurring. The staining patterns demonstrate reduced PKG expression at 7 days following injury in the proliferating neointimal cells compared with the medial cells (C and D). Cells demonstrating reduced PKG staining are beginning to demonstrate osteopontin staining (E) and have reduced calponin staining (F). For more information, see Ref. 2.

Regulation of PKG gene expression in VSMCs. It has been known for decades that PKG expression in mammalian cells is nonuniform, unlike the expression of PKG's closest relative, PKA. PKG expression is robust in all contractile smooth muscle cells and mesangial cells, platelets, and cerebellum; it is measurable in polymorphonuclear cells, endocrine secretory cells, heart, and some endothelial cells. It appears to be absent in skeletal muscle fibers, many neurons in the central nervous system, and erythrocytes. Other cell types may or may not express PKG, since the levels are so low that they probably reflect the levels in the vasculature. As mentioned earlier, PKG-null mice develop relatively normally and only acquire a lethal phenotype presumably from gastrointestinal disorders. If PKG, as the data suggest, is anything but a "house-keeping" gene, then there are important control mechanisms that enable its expression to be closely modulated.

Cultured VSMCs from rodent and rabbit vessels cease to express normal levels of PKG during multiple passaging; in many cases, expression drops to unmeasurable levels. The mechanism responsible for the decrease in PKG expression is unknown. High cell density appears to increase, or at least maintain, higher expression in vitro (25). Serum-derived growth factors such as platelet-derived growth factor may reduce PKG expression in vitro, suggesting that withdrawal of growth factors may enhance expression (101). Nevertheless, the molecular pathway leading to increased PKG levels in cultured cells or tissues is unknown at this time. In contrast, there is more information available on the mechanisms that decrease PKG expression. Soff et al. (98) demonstrated that high concentrations of NO donor drugs decrease the mRNA levels for PKG-Ialpha in primary cultures of bovine aortic smooth muscle cells. In the only intact tissue study performed to ask the same question, inducible NO synthase (iNOS) expression was found temporally and spatially correlated with decreased PKG expression (2). These results have led to our hypothesis that injury and inflammatory conditions that promote the production of inflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha are involved in the reduction in PKG expression in VSMCs (27, 62). We have postulated that these inflammatory cytokines induce the expression of iNOS and, by virtue of high and persistent NO output, inhibit PKG mRNA production. The drop in PKG expression coupled with the production of growth factors and other mediators of cell proliferation and inflammation then would allow modulation of VSMCs to the wound-healing phenotype. If this hypothesis is correct, then it would be predicted that animals deficient in iNOS would demonstrate reduced intimal lesion formation in response to injury. In fact, Chyu et al. (22) demonstrated that there was a dramatically reduced neointimal thickening after arterial wall injury in the iNOS knockout mouse.

The molecular mechanisms by which inflammatory events reduce PKG gene expression in VSMCs are unknown. It has been established that inflammatory cytokines induce not only iNOS expression but also expression of cyclooxygenase-2 (COX-2) in VSMCs and that both gene products have been shown to be abundant in atherosclerotic lesions (7, 4, 14, 26, 46, 50, 97, 99, 113, 116). One net effect of iNOS and COX-2 expression in the vessel wall in response to injury would be a sustained production of cyclic nucleotides (both cAMP and cGMP), resulting from the eicosanoid-dependent activation of adenylyl cyclase and the NO-dependent activation of guanylyl cyclase, respectively. Because cyclic nucleotide analogs have been shown to suppress PKG-I mRNA expression in cultured VSMCs (98), it is conceivable that high-output cyclic nucleotide production in response to inflammation suppresses PKG expression in the vessel wall in response to injury. Furthermore, cAMP analogs were found to be more potent than cGMP analogs in reducing PKG mRNA expression, suggesting that PKA may mediate the effects of both cAMP and cGMP through cross activation of PKA. A hypothetical model describing the role of iNOS, COX-2, and cyclic nucleotides in suppressing PKG expression is shown in Fig. 3. Clearly, more studies using pharmacological and molecular tools are needed to confirm whether these pathways in fact suppress PKG expression in vitro and in vivo.


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  		Fig. 3.   Model for the role of PKG in phenotypic modulation of vascular smooth muscle cells (VSMCs) in disease. Injury and inflammation lead to decreased PKG expression that, at least in part, regulates the phenotype of the VSMCs. Decreased PKG expression occurs as a result of direct suppression of the PKG gene by growth factors and cytokine inflammatory mediators. In the latter case, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha induce the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 in the vessel wall following injury. The resultant increases in cyclic nucleotide levels from nitric oxide (NO) and prostanoid molecules are shown to activate cAMP-dependent protein kinase (PKA). cGMP activates PKA through cross-activation. Through mechanisms not known at this point, it is proposed that PKA inhibits PKG mRNA production, resulting in modulation of the VSMC to the synthetic phenotype. bFGF, bovine fibroblast growth factor; PDGF, platelet-derived growth factor; PG, prostaglandin.

Interestingly, the promoter and gene structures of human PKG-I also suggest a possible role for PKA in regulating PKG mRNA expression. The published sequence of the human PKG-I gene (77) plus unpublished data from our laboratory suggest that PKG gene expression is driven by an Sp1-dependent mechanism. Sp1 proteins are ubiquitous transcription factors that either increase or decrease expression of genes (59). Previous studies have shown that Sp1 function is regulated by both NO (11, 108) and cAMP-dependent PKA activation (87, 105). These studies immediately suggest a link between iNOS and COX-2 induction and the decrease in PKG promoter activity, since inhibition of Sp1 activity by NO and PKA would decrease the expression of PKG in VSMCs. Alternatively, Sp1 proteins interact with a variety of coactivators and corepressors in many different cells. In VSMCs, Sp1 competes with the immediate early gene, egr-1, to increase the expression of other early-onset genes in response to injury (for example, platelet-derived growth factor-A chains, thrombospondin-1) (59, 94); egr-1 is repressed by a gene product, NAB2 (NGF1-A binding protein), to reduce the proliferate response in VSMCs (95). Therefore, it is possible that PKG-I gene expression is controlled by a factor or factors that interact with Sp1 or egr-1 and that NO and PKA regulate the activity of such proteins.


    CONCLUSIONS
TOP
ABSTRACT
INTRODUCTION
MECHANISMS OF SMOOTH MUSCLE...
REGULATION OF VSMC PHENOTYPE
CONCLUSIONS
REFERENCES

The NO signaling pathway has become one of the more intensely studied over the past decade. Although NO signaling in cells is complex as a result of its interactions with reactive oxygen species, heme groups on proteins, sulfhydryl groups, and other cellular targets, the activation of guanylyl cyclase remains the most important pathway in mediating NO function. The role of cGMP and its activation of PKG in smooth muscle relaxation has been intensively investigated for more than two decades. We now have a substantial amount of information regarding the mechanism of cGMP/PKG effects in smooth muscle relaxation. The role of NO/cGMP/PKG in smooth muscle cell proliferation and gene expression is now emerging as a major area of investigation. New knowledge on the mechanisms by which this pathway regulates VSMC growth and phenotype will surely add to our understanding on the development of vascular diseases and disorders from graft restenosis and atherosclerosis to hypertension.


    FOOTNOTES

Address for reprint requests and other correspondence: T. M. Lincoln, Dept. of Pathology, Division of Molecular and Cellular Pathology, Univ. of Alabama at Birmingham, Birmingham, AL 35294-0019 (E-mail: lincoln{at}path.uab.edu).


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MECHANISMS OF SMOOTH MUSCLE...
REGULATION OF VSMC PHENOTYPE
CONCLUSIONS
REFERENCES

1.   Alioua, A, Huggins P, and Rousseau E. PKG-I phosphorylates the alpha -subunit and upregulates reconstituted GKCa channels from tracheal smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 268: L1057-L1063, 1995[Abstract/Free Full Text].

2.   Anderson, PG, Boerth NJ, Liu M, McNamara DB, Cornwell JL, and Lincoln TM. Cyclic GMP-dependent protein kinase expression in coronary arterial smooth muscle in response to balloon catheter injury. Arterioscler Thromb Vasc Biol 20: 2192-2197, 2000[Abstract/Free Full Text].

3.   Archer, SL, Huang JMC, Hampl V, Nelson DP, Shultz PJ, and Weir EK. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci USA 91: 7583-7587, 1994[Abstract/Free Full Text].

4.   Baker, CS, Hall RJ, Evans TJ, Pomerance A, Maclouf J, Creminon C, Yacoub MH, and Polak JM. Cyclooxygenase-2 is widely expressed in atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages. Arterioscler Thromb Vasc Biol 19: 646-655, 1999[Abstract/Free Full Text].

5.   Beall, A, Bagwell D, Woodrum D, Stoming TA, Kato K, Suzuki A, Rasmussen H, and Brophy CM. The small heat shock-related protein, HSP20, is phosphorylated on serine 16 during cyclic nucleotide-dependent relaxation. J Biol Chem 274: 11344-11351, 1999[Abstract/Free Full Text].

6.   Beall, AC, Kato K, Goldenring JR, Rasmussen H, and Brophy CM. Cyclic nucleotide-dependent vasorelaxation is associated with the phosphorylation of a small heat shock-related protein. J Biol Chem 272: 11283-11287, 1997[Abstract/Free Full Text].

7.   Beasley, D, and Eldridge M. Interleukin 1beta and tumor necrosis factor alpha  synergistically induce nitric oxide synthase in rat vascular smooth muscle cells. Am J Physiol Regulatory Integrative Comp Physiol 266: R1197-R1215, 1994[Abstract/Free Full Text].

8.   Belsham, DD, and Mellon PL. Transcription factors Oct-1 and C/EBPbeta (CCAATT/enhancer-binding protein-beta ) are involved in the glutamate/nitric oxide/cyclic guanosine monophosphate-mediated repression of gonadotropin-releasing hormone gene expression. Mol Endocrinol 14: 212-228, 2000[Abstract/Free Full Text].

9.   Boerth, NJ, Cornwell TL, Dey N, and Lincoln TM. Cyclic GMP-dependent protein kinase regulates vascular smooth muscle cell phenotype. J Vasc Res 34: 245-259, 1997[Web of Science][Medline].

10.   Boerth, NJ, and Lincoln TM. Expression of the catalytic domain of cyclic GMP-dependent protein kinase in a baculovirus system. FEBS Lett 342: 255-260, 1994[Web of Science][Medline].

11.   Bogdan, C. Nitric oxide and the regulation of gene expression. Trends Cell Biol 11: 66-75, 2001[Web of Science][Medline].

12.   Brophy, CM, Dickinson M, and Woodrum D. Phosphorylation of the small heat shock-related protein, HSP20, in vascular smooth muscles is associated with changes in the macromolecular associations of HSP20. J Biol Chem 274: 6324-6329, 1999[Abstract/Free Full Text].

13.   Butt, E, Abel K, Krieger M, Palm D, Hoppe V, Hoppe J, and Walter U. cAMP- and cGMP-dependent protein kinase phosphorylation sites of the focal adhesion protein VASP in vitro and in intact human platelets. J Biol Chem 269: 14509-14517, 1994[Abstract/Free Full Text].

14.   Buttery, L, Springall DR, Chester AH, Evans TJ, Standfield N, Parums DV, Yacoub MH, and Polak JM. Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite. Lab Invest 75: 77-85, 1996[Web of Science][Medline].

15.   Campbell, JH, and Campbell GR. Smooth muscle cell phenotype changes in arterial wall homeostasis: implication for the pathogenesis of atherosclerosis. Exp Mol Pathol 42: 136-162, 1985.

16.   Casnellie, JE, and Greengard P. Guanosine 3':5'-cyclic monophosphate-dependent protein phosphorylation of endogenous substrate proteins in membranes of mammalian smooth muscle. Proc Natl Acad Sci USA 71: 1891-1895, 1974[Abstract/Free Full Text].

17.   Cavallini, L, Coassin M, Borean A, and Alexandre A. Prostacyclin and sodium nitroprusside inhibit the activity of the platelet inositol 1,4,5-trisphosphate receptor and promote its phosphorylation. J Biol Chem 271: 5545-5551, 1996[Abstract/Free Full Text].

18.   Chamley-Campbell, J, Campbell GR, and Ross R. Phenotype-dependent response of cultured aortic smooth muscle cells to serum mitogens. J Cell Biol 89: 379-383, 1981[Abstract/Free Full Text].

19.   Chamley-Campbell, J, Campbell GR, and Ross R. The smooth muscle cell in culture. Physiol Rev 59: 1-61, 1979[Free Full Text].

20.   Chen, Q, Tang HC, Barrans JD, Dzau VJ, Liew CC, and Pratt RE. Genomic analysis of human smooth muscle cell differentiation using high density microarrays (Abstract). Circulation 102, SupplII: 226, 2000.

21.   Chung, IM, Schwartz SM, and Murry CE. Clonal architecture of normal and atherosclerotic aorta: implications for atherogenesis and vascular development. Am J Pathol 152: 913-923, 1998[Abstract].

22.   Chyu, KY, Dimayuga P, Zhu J, Nilsson J, Kaul S, Shah PK, and Cercek B. Decreased neointimal thickening after arterial wall injury in inducible nitric oxide synthase knockout mice. Circ Res 85: 1192-1198, 1999[Abstract/Free Full Text].

23.   Collins, SP, and Uhler MD. Cyclic AMP- and cyclic GMP-dependent protein kinases differ in their regulation of cyclic AMP response element dependent gene transcription. J Biol Chem 274: 8391-8404, 1999[Abstract/Free Full Text].

24.   Cornwell, TL, Pryzwansky KB, Wyatt TA, and Lincoln TM. Regulation of sarcoplasmic reticulum phosphorylation by localized cyclic GMP-dependent protein kinase in vascular smooth muscle cells. Mol Pharmacol 40: 923-931, 1991[Abstract].

25.   Cornwell, TL, Soff GA, Traynor AE, and Lincoln TM. Regulation of the expression of cyclic GMP-dependent protein kinase by cell density in vascular smooth muscle cells. J Vasc Res 31: 330-337, 1994[Web of Science][Medline].

26.   Depre, C, Havaux X, Renkin J, Vanoverschelde JLJ, and Wijns W. Expression of inducible nitric oxide synthase in human coronary atherosclerotic plaque. Cardiovasc Res 41: 465-472, 1999[Abstract/Free Full Text].

27.   Dey, ND, Boerth NJ, Murphy-Ullrich JE, Chang P-L, Prince CW, and Lincoln TM. Cyclic GMP-dependent protein kinase inhibits osteopontine and thrombospondin production in rat aortic smooth muscle cells. Circ Res 82: 139-146, 1998[Abstract/Free Full Text].

28.   Draijer, R, Vaandrager AB, Nolte C, DeJong HR, Walter U, and van Hinsbergh VW. Expression of cGMP-dependent protein kinase I and phosphorylation of its substrate vasodilator-stimulated phosphoprotein, in human endothelial cells of different origin. Circ Res 77: 897-905, 1995[Abstract/Free Full Text].

29.   Eigenthaler, M, Lohmann SM, Walter U, and Pilz RB. Signal transduction by cGMP-dependent protein kinases and their emerging roles in the regulation of cell adhesion and gene expression. Rev Physiol Biochem Pharmacol 135: 173-209, 1999[Medline].

30.   Francis, SH, and Corbin JD. Structure and function of cyclic nucleotide-dependent protein kinases. Annu Rev Physiol 56: 237-272, 1994[Web of Science][Medline].

31.   Fukao, M, Mason HS, Britton FC, Kenyon JL, Horowitz B, and Keef KD. Cyclic GMP-dependent protein kinase activates cloned BKCa channels expressed in mammalian cells by direct phosphorylation at serine 1072. J Biol Chem 274: 10927-10935, 1999[Abstract/Free Full Text].

32.   Fukumoto, S, Koyama H, Hosoe M, Yamakawa K, Tanaka S, Morii H, and Nishizawa Y. Distinct role of cAMP and cGMP in cell cycle control of vascular smooth muscle cells: cGMP delays cell cycle transition through suppression of cyclin D1 and cyclin-dependent kinase 4 activation. Circ Res 85: 985-991, 1999[Abstract/Free Full Text].

33.   Garg, UC, and Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 83: 1774-1777, 1989.

34.   Gertzberg, N, Clements R, Jaspers I, Ferro TJ, Neumann P, Flescher E, and Johnson A. Tumor necrosis factor-alpha induced activating protein-1 is modulated by nitric oxide-mediated protein kinase G activation. Am J Respir Cell Mol Biol 22: 105-115, 2000[Abstract/Free Full Text].

35.   Gong, MC, Iizuka K, Nixon G, Browne JP, Hall A, Eccleston JF, Sugai M, Kobayashi S, Somlyo AV, and Somlyo AP. Role of guanosine nucleotide-binding proteins---ras family or trimeric proteins or both---in Ca2+ sensitization in smooth muscle. Proc Natl Acad Sci USA 93: 1340-1345, 1996[Abstract/Free Full Text].

36.   Gown, AM, Tsukada T, and Ross R. Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol 125: 191-207, 1986[Abstract].

37.   Gu, M, and Brecher P. Nitric oxide-induced increase in p21 (Sdi1/Cip1/Waf1) expression during the cell cycle in adventitial fibroblasts. Arterioscler Thromb Vasc Biol 20: 27-34, 2000[Abstract/Free Full Text].

38.   Gu, M, Lynch J, and Brecher P. Nitric oxide increases p21(Waf1/Cip1) expression by a cyclic GMP-dependent pathway that includes activation of extracellular signal-regulated kinase and p70 (S6K). J Biol Chem 275: 11389-11396, 2000[Abstract/Free Full Text].

39.   Gudi, T, Huvar I, Meinecke M, Lohmann SM, Boss GR, and Pilz RB. Regulation of gene expression by cGMP-dependent protein kinase: transactivation of the c-fos promoter. J Biol Chem 271: 4597-4600, 1996[Abstract/Free Full Text].

40.   Gudi, T, Lohmann SM, and Pilz RB. Regulation of gene expression by cyclic GMP-dependent protein kinase requires nuclear translocation of the kinase: identification of a nuclear localization signal. Mol Cell Biol 17: 5244-5254, 1997[Abstract].

41.   Haby, C, Lisovoski F, Aunis D, and Zwiller J. Stimulation of cyclic GMP pathway by NO induces expression of the immediate early genes c-fos and junB in PC12 cells. J Neurochem 62: 496-501, 1994[Web of Science][Medline].

42.   Han, CI, Campbell GR, and Campbell JH. Circulating bone marrow cells can contribute to neointimal formation. J Vasc Res 38: 113-119, 2001[Web of Science][Medline].

43.   Haug, LS, Jensen V, Hvalby O, Walaas SI, and Ostvold AC. Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic nucleotide-dependent protein kinases in vitro and in rat cerebellar slices in situ. J Biol Chem 274: 7467-7473, 1999[Abstract/Free Full Text].

44.   Hofmann, F, Ammendola A, and Schlossmann J. Rising behind NO: cGMP-dependent protein kinase. J Cell Sci 113: 1671-1676, 2000[Abstract].

45.   Huang, PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, and Fishman MC. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377: 239-242, 1995[Medline].

46.   Husain, S, Andrews NP, Mulcahy D, Panza JA, and Quyyumi AA. Aspirin improves endothelial dysfunction in atherosclerosis. Circulation 97: 716-720, 1998[Abstract/Free Full Text].

47.   Idriss, AD, Gudi T, Casteel DE, Kharitonov VG, Pilz RB, and Boss GR. Nitric oxide regulation of gene transcription via soluble guanylate cyclase and type I cGMP-dependent protein kinase. J Biol Chem 274: 9489-9493, 1999[Abstract/Free Full Text].

48.   Immenschuh, S, Hinke V, Ohlmann A, Gifhorn-Katz S, Katz N, Jungermann K, and Kietzmann T. Transcriptional activation of the haem oxygenase-1 gene by cGMP via a cAMP response element/activator protein-1 element in primary cultures of rat hepatocytes. Biochem J 334: 141-146, 1998.

49.   Johnson, RM, and Lincoln TM. Effects of nitroprusside, glyceryl trinitrate and 8-bromo-cyclic GMP on phosphorylase a formation and myosin light chain. Mol Pharmacol 27: 333-342, 1985[Abstract].

50.   Joly, GA, Schini VB, and Vanhoutte PM. Balloon injury and interleukin 1 beta induce nitric oxide synthase activity in rat carotid arteries. Circ Res 71: 331-338, 1992[Abstract/Free Full Text].

51.   Karczewski, T, Kelm M, Hartmann M, and Schrader J. Role of phospholamban in NO/EDRF-induced relaxation in rat aorta. Life Sci 51: 1205-1210, 1992[Web of Science][Medline].

52.   Kawada, T, Toyosato A, Islam O, Yoshida Y, and Imai S. cGMP-kinase mediates cGMP- and cAMP-induced Ca desensitization of skinned rat artery. Eur J Pharmacol 323: 75-82, 1997[Web of Science][Medline].

53.   Kibbe, MR, Li J, Nie S, Watkins SC, Lizonova A, Kovesdi I, Simmons RL, Billar TR, and Tzeng E. Inducible nitric oxide synthase (iNOS) expression upregulates p21 and inhibits vascular smooth muscle cell proliferation through p42/p44 mitogen-activated protein kinase activation and independent of p53 and cyclic guanosine monophosphate. J Vasc Surg 31: 1214-1228, 2000[Web of Science][Medline].

54.   Kimura, K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, and Kaibuchi K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273: 245-248, 1966[Abstract].

55.   Koga, T, Yoshida Y, Cai JQ, and Imai S. Purification and characterization of a 240-kDa cGMP-dependent protein kinase substrate of vascular smooth muscle: close resemblance to inositol 1,4,5-trisphosphate receptor. J Biol Chem 269: 11640-11647, 1994[Abstract/Free Full Text].

56.   Komalavilas, P, and Lincoln TM. Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic GMP-dependent protein kinase. J Biol Chem 269: 8701-8707, 1994[Abstract/Free Full Text].

57.   Komalavilas, P, and Lincoln TM. Phosphorylation of the inositol 1,4,5-trisphosphate receptor: cyclic GMP-dependent protein kinase mediates cAMP and cGMP dependent phosphorylation in the intact rat aorta. J Biol Chem 271: 21933-21938, 1996[Abstract/Free Full Text].

58.   Kroncke, KD, and Carlberg C. Inactivation of zinc finger transcription factors provides a mechanism for a gene regulatory role of nitric oxide. FASEB J 13: 166-173, 2000.

59.   Lania, L, Majello B, and De Luca P. Transcription and regulation of SP family proteins. Int J Biochem Cell Biol 29: 1313-1323, 1997[Web of Science][Medline].

60.   Lee, MR, Li L, and Kitazawa T. Cyclic GMP causes Ca desensitization in vascular smooth muscle by activating the myosin light chain phosphatase. J Biol Chem 272: 5063-5068, 1997[Abstract/Free Full Text].

61.   Lincoln, TM. Effects of nitroprusside and 8-bromo-cyclic GMP on the contractile activity of the rat aorta. J Pharmacol Exp Ther 224: 100-107, 1983[Free Full Text].

62.   Lincoln, TM, Dey NB, Boerth NJ, Cornwell TL, and Soff GA. Nitric oxide-cyclic GMP pathway regulates vascular smooth muscle cell phenotypic modulation: implications in vascular diseases. Acta Physiol Scand 164: 507-515, 1998[Web of Science][Medline].

63.   Lincoln, TM, and Komalavilas P. Cyclic GMP-mediated signaling mechanisms in smooth muscle. In: Nitric Oxide, edited by Ignarro LJ.. New York: Academic, 2000, p. 401-4425.

64.   Liu, XK, Abernethy DR, and Andrawis NS. Nitric oxide inhibits Oct-1 binding activity in cultured vascular smooth muscle cells. Life Sci 62: 739-749, 1998[Web of Science][Medline].

65.   Lohmann, SM, Vaandrager AB, Smolenski A, Walter U, and DeJonge HR. Distinct and specific functions of cGMP-dependent protein kinases. Trends Biochem Sci 22: 307-312, 1997[Web of Science][Medline].

66.   Luo, DL, Nakazawa M, Ishibashi T, Kato K, and Imai S. Putative selective inhibitors of the sarcoplasmic reticulum Ca2+-pump ATPase inhibit relaxation by nitroglycerine and atrial natriuretic factor of the rabbit aorta contracted by phenylephrine. J Pharmacol Exp Ther 265: 1187-1192, 1993[Abstract/Free Full Text].

67.   Majesky, MW, Giachelli CM, Reidy MA, and Schwartz SM. Rat carotid neointimal smooth muscle cells re-express a developmentally regulated phenotype during repair of arterial injury. Circ Res 71: 759-768, 1992[Abstract/Free Full Text].

68.   McNamara, DB, Bedi B, Aurora H, Tena L, Ignarro LJ, Kadowitz PJ, and Akers DL. L-Arginine inhibits balloon catheter-induced intimal hyperplasia. Biochem Biophys Res Commun 193: 291-296, 1993[Web of Science][Medline].

69.   Miura, Y, Kaibuchi K, Itoh T, Francis SF, and Corbin JD. Phosphorylation of smg p21B/rap1B p21 by cyclic GMP-dependent protein kinase. FEBS Lett 297: 171-174, 1992[Web of Science][Medline].

70.   Mosse, PR, Campbell GR, Wang ZL, and Campbell JH. Smooth muscle phenotypic expression in human carotid arteries. I. Comparison of cells from diffuse intimal thickenings adjacent to atheromatous plaques with those of the media. Lab Invest 53: 556-562, 1985[Web of Science][Medline].

71.   Mundian-Weilenmann, C, Vittone L, Rinaldi G, Said M, deCingolani GC, and Mattiazzi A. Endoplasmic reticulum contribution to the relaxant effect of cGMP- and cAMP-elevating agents in feline aorta. Am J Physiol Heart Circ Physiol 278: H1856-H1865, 2000[Abstract/Free Full Text].

72.   Murthy, KS, and Makhlouf GM. Interaction of cA-kinase and cG-kinase in mediating relaxation of dispersed smooth muscle cells. Am J Physiol Cell Physiol 268: C171-C180, 1995[Abstract/Free Full Text].

73.   Murthy, KS, Severi C, Grider JR, and Makhlouf GM. Inhibition of IP3 an IP3-dependent Ca2+ mobilization by cyclic nucleotides in isolated gastric muscle cells. Am J Physiol Gastrointest Liver Physiol 264: G967-G974, 1993[Abstract/Free Full Text].

74.   Murphy-Ullrich, JE, Pallero MA, Boerth N, Greenwood JA, Lincoln TM, and Cornwell TL. Cyclic GMP-dependent protein kinase is required for thrombospondin and tenascin mediated focal adhesion disassembly. J Cell Sci 109: 2499-2508, 1996[Abstract].

75.   Nelson, MT, Cheng H, Rubart M, Santana LF, Bonev AD, Knot HJ, and Lederer WJ. Relaxation of arterial smooth muscle by calcium sparks. Science 270: 633-637, 1995[Abstract/Free Full Text].

76.   Nishimura, N, and van Breemen C. Direct regulation of smooth muscle contractile elements by second messengers. Biochem Biophys Res Commun 163: 929-935, 1989[Web of Science][Medline].

77.   Orstavik, S, Natarajan V, Tasken K, Jahnsen T, and Sandberg M. Characterization of the human gene encoding the type I alpha and I beta cGMP-dependent protein kinase (PRKG1). Genomics 42: 311-318, 1997[Web of Science][Medline].

78.   Owens, GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 75: 487-517, 1995[Abstract/Free Full Text].

79.   Owens, GK. Molecular control of vascular smooth muscle cell differentiation. Acta Physiol Scand 164: 623-635, 1998[Web of Science][Medline].

80.   Peunova, N, and Enlkolopov G. Amplification of calcium-induced gene transcription by nitric oxide in neuronal cells. Nature 364: 450-453, 1993[Medline].

81.   Pfeifer, A, Klatt P, Massberg S, Ny L, Sausbier M, Hirneiss C, Wang GX, Korth M, Aszodi A, Andersson KE, Krombach F, Mayerhofer A, Ruth P, Fassler R, and Hofmann F. Defective smooth muscle regulation in cGMP kinase I-deficient mice. EMBO J 11: 3045-3051, 1998[Web of Science][Medline].

82.   Pilz, R, Suhasini M, Idrissi S, Meinkoth JL, and Boss GR. Nitric oxide and cGMP analogs activate transcription from AP-1-responsive promoters in mammalian cells. FASEB J 9: 552-558, 1995[Abstract].

83.   Porter, VA, Bonev AD, Knot HJ, Heppner TJ, Stevenson AS, Kleppisch T, Lederer WJ, and Nelson MT. Frequency modulation of Ca sparks is involved in regulation of arterial diameter by cyclic nucleotides. Am J Physiol Cell Physiol 274: C1346-C1355, 1998[Abstract/Free Full Text].

84.   Reinhard, M, Giehl K, Abel K, Haffner C, Jarchau T, Hoppe V, Jockusch BM, and Walter U. The proline rich focal adhesion and microfilament protein VASP is a ligand for profilins. EMBO J 14: 1583-1589, 1995[Web of Science][Medline].

85.   Reinhard, M, Halbrugge M, Scheer U, Wiegand C, Jockusch BM, and Walter U. The 46/50 kDa phosphoprotein VASP purified from human platelets is a novel protein associated with actin filaments and focal contacts. EMBO J 11: 2063-2070, 1992[Web of Science][Medline].

86.   Rembold, CM, Foster DB, Strauss JD, Wingard CJ, and Eyk JE. cGMP-mediated phosphorylation of heat shock protein 20 may cause smooth muscle relaxation without myosin light chain dephosphorylation in swine carotid artery. J Physiol (Lond) 524: 865-878, 2000[Abstract/Free Full Text].

87.   Rohlff, C, Ahmad S, Borellini F, Lei J, and Glazer RI. Modulation of transcription factor Sp1 by cAMP-dependent protein kinase. J Biol Chem 272: 21137-21141, 1997[Abstract/Free Full Text].

88.   Sappino, AP, Schnrch W, and Gabbiani G. Biology of Disease. Differentiation repetoire of fibroblastic cells: expression of cytoskeletal proteins as marker of phenotypic modulations. Lab Invest 63: 144-161, 1990[Web of Science][Medline].

89.   Sarcevic, B, Brookes V, Martin TJ, Kemp B, and Robinson PJ. Atrial natriuretic peptide-dependent phosphorylation of smooth muscle cell particulate fraction proteins is mediated by cGMP-dependent protein kinase. J Biol Chem 264: 20648-20654, 1989[Abstract/Free Full Text].

90.   Sauzeau, V, LeJeune H, Cario-Toumaniantz C, Smolenski A, Lohmann SM, Bertoglio J, Chardin P, Pacaud P, and Loirand G. Cyclic GMP-dependent protein kinase signaling pathway inhibits Rho-A-induced Ca sensitization of contraction in vascular smooth muscle. J Biol Chem 275: 21722-21729, 2000[Abstract/Free Full Text].

91.   Schlossmann, J, Ammendola A, Ashman K, Zong X, Huber A, Neubauer G, Wang GX, Allescher HD, Korth M, Wilm M, Hofmann F, and Ruth P. Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta . Nature 404: 197-201, 2000[Medline].

92.   Schwartz, M, O'Brien ER, deBlois D, and Giachelli CM. Relevance of smooth muscle replication and development to vascular disease. In: The Vascular Smooth Muscle Cell, edited by Schwartz SM, and Mecham RP.. New York: Academic, 1995, p. 81-139.

93.   Sciorati, C, Nistico G, Meldolesi J, and Clementi E. Nitric oxide effects on cell growth: cGMP-dependent stimulation of the AP-1 transcription complex and cyclic GMP-independent slowing of cell cycling. Br J Pharmacol 122: 687-697, 1997[Web of Science][Medline].

94.   Silverman, ES, and Collins T. Pathways of Egr-1-mediated gene transcription in vascular biology. Am J Pathol 154: 665-670, 1999[Free Full Text].

95.   Silverman, ES, Khachigan LM, Santiago FS, Williams AJ, Lindner V, and Collins T. Vascular smooth muscle cells express the transcriptional corepressor NAB2 in response to injury. Am J Pathol 155: 1311-1317, 1999[Abstract/Free Full Text].

96.   Smolenski, A, Poller W, Walter U, and Lohmann SM. Regulation of human endothelial cell focal adhesion sites and migration by cGMP-dependent protein kinase I. J Biol Chem 275: 25723-25732, 2000[Abstract/Free Full Text].

97.   Sobey, CG, Brooks RM, and Heistad DD. Evidence that expression of inducible nitric oxide synthase in response to endotoxin is augmented in atherosclerotic rabbits. Circ Res 77: 536-543, 1995[Abstract/Free Full Text].

98.   Soff, GA, Corrnwell TL, Cundiff DL, Gately S, and Lincoln TM. Smooth muscle cell expression of type I cyclic-GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cAMP. J Clin Invest 100: 2580-2587, 1997[Web of Science][Medline].

99.   Speir, E, Yu ZX, Ferrans VJ, Huang ES, and Epstein SE. Aspirin attenuates cytomegalovirus infectivity and gene expression mediated by cyclooxygenase-2 in coronary artery smooth muscle cells. Circ Res 83: 210-216, 1998[Abstract/Free Full Text].

100.   Surks, HK, Mochizuki N, Kasai Y, Georgescu SP, Tang KM, Ito M, Lincoln TM, and Mendelsohn ME. Regulation of myosin phosphatase by a specific interaction with cGMP-dependent protein kinase Ialpha . Science 286: 1583-1587, 1999[Abstract/Free Full Text].

101.   Tamura, H, Itoh H, Ogawa Y, Nakagawa O, Harada M, Chun TW, Suga S, Yoshimasa T, and Nakao K. cDNA cloning and gene expression of human type Ialpha cGMP-dependent protein kinase. Hypertension 27: 552-557, 1996[Abstract/Free Full Text].

102.   Tanner, FC, Meier P, Greutert H, Champion C, Nabel EG, and Luscher TF. Nitric oxide modulates expression of cell cycle regulatory proteins: a cytostatic strategy for inhibition of human vascular smooth muscle cell proliferation. Circulation 101: 1982-1989, 2000[Abstract/Free Full Text].

103.   Torrecillas, G, Diez-Marques ML, Garcia-Escribano C, Bosch RJ, Rodriguez-Puyol D, and Rodriguez-Puyol M. Mechanisms of cGMP-dependent mesangial cell relaxation: a role for myosin light chain phosphatase activation. Biochem J 346: 217-222, 2000.

104.   Van Riper, DA, McDaniel NL, and Rembold CM. Myosin light chain kinase phosphorylation in nitrovasodilator induced swine carotid artery relaxation. Biochim Biophys Acta 1355: 323-330, 1997[Medline].

105.   Venepally, P, and Waterman MR. Two Sp1-binding sites mediate cAMP-induced transcription of the bovine CYP11A gene through the protein kinase A signaling pathway. J Biol Chem 270: 25402-25410, 1995[Abstract/Free Full Text].

106.   Von Lintig, FC, Pilz RB, and Boss GR. Quantitative determination of Rap 1 activation in cyclic nucleotide-treated HL-60 leukemic cells: lack of Rap 1 activation in variant cells. Oncogene 19: 4029-4034, 2000[Web of Science][Medline].

107.   Wang, X, Bruderer S, Rafi Z, Xue J, Milburn PJ, Kramer A, and Robinson PJ. Phosphorylation of splicing factor SF1 on ser20 by cGMP-dependent protein kinase regulates spliceosome assembly. EMBO J 18: 4549-4559, 1999[Web of Science][Medline].

108.   Wang, S, Wang W, Wesley RA, and Danner RL. A Sp1 binding site of the tumor necrosis factor alpha  promoter functions as a nitric oxide response element. J Biol Chem 274: 33190-33193, 1999[Abstract/Free Full Text].

109.   Watanabe, M, Layne MD, Hsieh CM, Jain MK, Chen Q, Pratt RE, Yet SF, Perrella MA, and Lee ME. Induction of type I cGMP-dependent protein kinase during the differentiation of a neural crest derived precursor cell line to the smooth muscle cell lineage. Circulation 102, Suppl II: 226, 2000.

110.   Wellman, GC, Eckman DM, Santana LF, Heppner TJ, Kranias EG, and Nelson MT. Protein kinase A increases Ca spark frequency both through effects on phsopholamban and on ryanodine receptors (RyR) in intact mouse cerebral arteries (Abstract). FASEB J 13: A1034, 1999.

111.   White, R, Lee A, Shcherbatko AD, Lincoln TM, Schonbrunn A, and Armstrong DL. Potassium channel stimulation by natriuretic peptides through cGMP-dependent dephosphorylation. Nature 361: 263-266, 1993[Medline].

112.   Wilcox, JN, Cipolla GD, Martin FH, Simonet L, Dunn B, Ross CE, and Scott NA. Contribution of adventitial myofibroblasts to vascular remodeling and lesion formation after experimental angioplasty in pig coronary arteries. Ann NY Acad Sci 811: 437-447, 1997[Web of Science][Medline].

113.   Wilcox, JN, Subramanian RR, Sundell CL, Ross TW, Pollock JS, Harrison DG, and Marsden PA. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol 17: 2479-2488, 1997[Abstract/Free Full Text].

114.   Wu, X, Haystead TA, Nakamoto RK, Somlyo AV, and Somlyo AP. Acceleration of myosin light chain dephosphorylation and relaxation of smooth muscle by telokin: synergism with cyclic nucleotide activated kinase. J Biol Chem 273: 11362-11369, 1998[Abstract/Free Full Text].

115.   Yamboliev, IA, Hedges JC, Mutnick JL, Adam LP, and Gerthoffer WT. Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27 pathway. Am J Physiol Heart Circ Physiol 278: H1899-H1907, 2000[Abstract/Free Full Text].

116.   Yan, ZQ, and Hansson GK. Overexpression of inducible nitric oxide synthase by neointimal smooth muscle cells. Circ Res 82: 21-29, 1998[Abstract/Free Full Text].

117.   Zhou, X-B, Ruth P, Schlossmann J, Hofmann F, and Korth M. Protein phosphatase 2A is essential for the activation of Ca2+-activated K+ currents by cGMP-dependent protein kinase in tracheal smooth muscle and Chinese hamster ovary cells. J Biol Chem 271: 19760-19767, 1996[Abstract/Free Full Text].

J APPL PHYSIOL 91(3):1421-1430
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[Abstract] [Full Text] [PDF]

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[Abstract] [Full Text] [PDF]

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[Abstract] [Full Text] [PDF]

Home page
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[Abstract] [Full Text] [PDF]

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[Abstract] [Full Text] [PDF]

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[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. Bonnevier, R. Fassler, A. P. Somlyo, A. V. Somlyo, and A. Arner
Modulation of Ca2+ Sensitivity by Cyclic Nucleotides in Smooth Muscle from Protein Kinase G-deficient Mice
J. Biol. Chem., February 13, 2004; 279(7): 5146 - 5151.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Q. Q. Huang, S. A. Fisher, and F. V. Brozovich
Unzipping the Role of Myosin Light Chain Phosphatase in Smooth Muscle Cell Relaxation
J. Biol. Chem., January 2, 2004; 279(1): 597 - 603.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
T. Chitapanarux, S. L. Chen, H. Lee, A. C. Melton, and H. F. Yee Jr.
C-type natriuretic peptide induces human colonic myofibroblast relaxation
Am J Physiol Gastrointest Liver Physiol, January 1, 2004; 286(1): G31 - G36.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
R. B. Pilz and D. E. Casteel
Regulation of Gene Expression by Cyclic GMP
Circ. Res., November 28, 2003; 93(11): 1034 - 1046.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
U. Hink, M. Oelze, P. Kolb, M. Bachschmid, M.-H. Zou, A. Daiber, H. Mollnau, M. August, S. Baldus, N. Tsilimingas, et al.
Role for peroxynitrite in the inhibition of prostacyclin synthase in nitrate tolerance
J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1826 - 1834.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
R. Feil, S. M. Lohmann, H. de Jonge, U. Walter, and F. Hofmann
Cyclic GMP-Dependent Protein Kinases and the Cardiovascular System: Insights From Genetically Modified Mice
Circ. Res., November 14, 2003; 93(10): 907 - 916.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
W. Wolfsgruber, S. Feil, S. Brummer, O. Kuppinger, F. Hofmann, and R. Feil
A proatherogenic role for cGMP-dependent protein kinase in vascular smooth muscle cells
PNAS, November 11, 2003; 100(23): 13519 - 13524.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
T. Munzel, R. Feil, A. Mulsch, S. M. Lohmann, F. Hofmann, and U. Walter
Physiology and Pathophysiology of Vascular Signaling Controlled by Cyclic Guanosine 3',5'-Cyclic Monophosphate-Dependent Protein Kinase
Circulation, November 4, 2003; 108(18): 2172 - 2183.
[Full Text] [PDF]

Home page
 Circ. Res.Home page
V. Gerzanich, A. Ivanov, S. Ivanova, J. B. Yang, H. Zhou, Y. Dong, and J. M. Simard
Alternative Splicing of cGMP-Dependent Protein Kinase I in Angiotensin-Hypertension: Novel Mechanism for Nitrate Tolerance in Vascular Smooth Muscle
Circ. Res., October 31, 2003; 93(9): 805 - 812.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
A. L. Kleschyov, M. Oelze, A. Daiber, Y. Huang, H. Mollnau, E. Schulz, K. Sydow, B. Fichtlscherer, A. Mulsch, and T. Munzel
Does Nitric Oxide Mediate the Vasodilator Activity of Nitroglycerin?
Circ. Res., October 31, 2003; 93 (9): e104 - e112.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. Airhart, Y.-F. Yang, C. T. Roberts Jr., and M. Silberbach
Atrial Natriuretic Peptide Induces Natriuretic Peptide Receptor-cGMP-dependent Protein Kinase Interaction
J. Biol. Chem., October 3, 2003; 278(40): 38693 - 38698.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
G. G. Geary and J. N. Buchholz
Selected Contribution: Effects of aging on cerebrovascular tone and [Ca2+]i
J Appl Physiol, October 1, 2003; 95(4): 1746 - 1754.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
F. J. Rivero-Vilches, S De Frutos, M Saura, D Rodriguez-Puyol, and M Rodriguez-Puyol
Differential relaxing responses to particulate or soluble guanylyl cyclase activation on endothelial cells: a mechanism dependent on PKG-I{alpha} activation by NO/cGMP
Am J Physiol Cell Physiol, October 1, 2003; 285(4): C891 - C898.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
Y. Gao, S. Dhanakoti, E. M. Trevino, F. C. Sander, A. M. Portugal, and J. U. Raj
Effect of oxygen on cyclic GMP-dependent protein kinase-mediated relaxation in ovine fetal pulmonary arteries and veins
Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L611 - L618.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
X. Wang, G. Trottier, and R. Loutzenhiser
Determinants of renal afferent arteriolar actions of bradykinin: evidence that multiple pathways mediate responses attributed to EDHF
Am J Physiol Renal Physiol, September 1, 2003; 285(3): F540 - F549.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. W. Park and L.-N. Wei
Regulation of c-myc Gene by Nitric Oxide via Inactivating NF-{kappa}B Complex in P19 Mouse Embryonal Carcinoma Cells
J. Biol. Chem., August 8, 2003; 278(32): 29776 - 29782.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
T. C. Resta
Hypoxic regulation of nitric oxide signaling in vascular smooth muscle
Am J Physiol Lung Cell Mol Physiol, August 1, 2003; 285(2): L293 - L295.
[Full Text] [PDF]

Home page
 DiabetesHome page
S. Wang, X. Wu, T. M. Lincoln, and J. E. Murphy-Ullrich
Expression of Constitutively Active cGMP-Dependent Protein Kinase Prevents Glucose Stimulation of Thrombospondin 1 Expression and TGF-{beta} Activity
Diabetes, August 1, 2003; 52(8): 2144 - 2150.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
C. J. Mingone, S. A. Gupte, T. Iesaki, and M. S. Wolin
Hypoxia enhances a cGMP-independent nitric oxide relaxing mechanism in pulmonary arteries
Am J Physiol Lung Cell Mol Physiol, August 1, 2003; 285(2): L296 - L304.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
T. Matsumoto, L. V. d'uscio, D. Eguchi, M. Akiyama, L. A. Smith, and Z. S. Katusic
Protective Effect of Chronic Vitamin C Treatment on Endothelial Function of Apolipoprotein E-Deficient Mouse Carotid Artery
J. Pharmacol. Exp. Ther., July 1, 2003; 306(1): 103 - 108.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
K. S. Murthy, H. Zhou, J. R. Grider, and G. M. Makhlouf
Inhibition of sustained smooth muscle contraction by PKA and PKG preferentially mediated by phosphorylation of RhoA
Am J Physiol Gastrointest Liver Physiol, June 1, 2003; 284(6): G1006 - G1016.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Hou, J. Lascola, N. O. Dulin, R. D. Ye, and D. D. Browning
Activation of cGMP-dependent Protein Kinase by Protein Kinase C
J. Biol. Chem., May 2, 2003; 278(19): 16706 - 16712.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
V. Gerzanich, S. Ivanova, H. Zhou, and J. M. Simard
Mislocalization of eNOS and Upregulation of Cerebral Vascular Ca2+ Channel Activity in Angiotensin-Hypertension
Hypertension, May 1, 2003; 41(5): 1124 - 1130.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
V. Sauzeau, M. Rolli-Derkinderen, C. Marionneau, G. Loirand, and P. Pacaud
RhoA Expression Is Controlled by Nitric Oxide through cGMP-dependent Protein Kinase Activation
J. Biol. Chem., March 7, 2003; 278(11): 9472 - 9480.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
K. S. Murthy and H. Zhou
Selective phosphorylation of the IP3R-I in vivo by cGMP-dependent protein kinase in smooth muscle
Am J Physiol Gastrointest Liver Physiol, February 1, 2003; 284(2): G221 - G230.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
B. Adegunloye, E. Lamarre, and R. S. Moreland
Quinine Inhibits Vascular Contraction Independent of Effects on Calcium or Myosin Phosphorylation
J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 294 - 300.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
I. Fleming and R. Busse
Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R1 - R12.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. P. Bracamonte, M. Jayachandran, K. S. Rud, and V. M. Miller
Acute effects of 17beta -estradiol on femoral veins from adult gonadally intact and ovariectomized female pigs
Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2389 - H2396.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
A. J Wilson and L. H Clapp
The molecular site of action of KATP channel inhibitors determines their ability to inhibit iNOS-mediated relaxation in rat aorta
Cardiovasc Res, October 1, 2002; 56(1): 154 - 163.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Gudi, J. C. Chen, D. E. Casteel, T. M. Seasholtz, G. R. Boss, and R. B. Pilz
cGMP-dependent Protein Kinase Inhibits Serum-response Element-dependent Transcription by Inhibiting Rho Activation and Functions
J. Biol. Chem., September 27, 2002; 277(40): 37382 - 37393.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L.-M. Postovit, M. A. Adams, G. E. Lash, J. P. Heaton, and C. H. Graham
Oxygen-mediated Regulation of Tumor Cell Invasiveness. INVOLVEMENT OF A NITRIC OXIDE SIGNALING PATHWAY
J. Biol. Chem., September 13, 2002; 277(38): 35730 - 35737.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. E. Casteel, S. Zhuang, T. Gudi, J. Tang, M. Vuica, S. Desiderio, and R. B. Pilz
cGMP-dependent Protein Kinase Ibeta Physically and Functionally Interacts with the Transcriptional Regulator TFII-I
J. Biol. Chem., August 23, 2002; 277(35): 32003 - 32014.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Wang, M. Eto, W. D. Steers, A. P. Somlyo, and A. V. Somlyo
RhoA-mediated Ca2+ Sensitization in Erectile Function
J. Biol. Chem., August 16, 2002; 277(34): 30614 - 30621.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
R. Feil, N. Gappa, M. Rutz, J. Schlossmann, C. R. Rose, A. Konnerth, S. Brummer, S. Kuhbandner, and F. Hofmann
Functional Reconstitution of Vascular Smooth Muscle Cells With cGMP-Dependent Protein Kinase I Isoforms
Circ. Res., May 31, 2002; 90(10): 1080 - 1086.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
H. Sellak, X. Yang, X. Cao, T. Cornwell, G. A. Soff, and T. Lincoln
Sp1 Transcription Factor as a Molecular Target for Nitric Oxide- and Cyclic Nucleotide-Mediated Suppression of cGMP-Dependent Protein Kinase-I{alpha} Expression in Vascular Smooth Muscle Cells
Circ. Res., March 8, 2002; 90(4): 405 - 412.
[Abstract] [Full Text] [PDF]

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