HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (20) Citing Articles via Google Scholar Google Scholar Articles by Mauban, J. R. H. Articles by Yuan, J. X.-J. Search for Related Content PubMed PubMed Citation Articles by Mauban, J. R. H. Articles by Yuan, J. X.-J.

INVITED REVIEW

HIGHLIGHTED TOPICS
Pulmonary Circulation and Hypoxia

Hypoxic pulmonary vasoconstriction: role of ion channels

Department of Medicine, University of California, San Diego, La Jolla, California

	ABSTRACT

TOP ABSTRACT ROLE OF [Ca2+]cyt IN... ROLE OF K+ CHANNELS... ROLE OF SR Ca2+... ROLE OF STORE-OPERATED Ca2+... SUMMARY AND FUTURE RESEARCH GRANTS ACKNOWLEDGMENTS REFERENCES

 
Acute hypoxia induces pulmonary vasoconstriction and chronic hypoxia causes structural changes of the pulmonary vasculature including arterial medial hypertrophy. Electro- and pharmacomechanical mechanisms are involved in regulating pulmonary vasomotor tone, whereas intracellular Ca²⁺ serves as an important signal in regulating contraction and proliferation of pulmonary artery smooth muscle cells. Herein, we provide a basic overview of the cellular mechanisms involved in the development of hypoxic pulmonary vasoconstriction. Our discussion focuses on the roles of ion channels permeable to K⁺ and Ca²⁺, membrane potential, and cytoplasmic Ca²⁺ in the development of acute hypoxic pulmonary vasoconstriction and chronic hypoxia-mediated pulmonary vascular remodeling.

hypoxia; proliferation; remodeling; calcium

On the basis of the Poiseuille principle, PVR is inversely proportional to the fourth power of the radius of the pulmonary artery. Therefore, small changes in the radius of pulmonary arteries (especially small arteries and arterioles) can significantly change PVR. Pulmonary vasoconstriction, vascular remodeling (characterized with medial and intimal hypertrophy), and in situ thrombosis are three major factors that can decrease the radius of pulmonary vessels and increase PVR and, ultimately, PAP.

Experiments in vitro demonstrate that acute hypoxia causes constriction in isolated pulmonary arteries with or without intact endothelium and induces contraction in isolated pulmonary artery smooth muscle cells (PASMC) via changes in membrane potential (E_m), cytosolic free Ca²⁺ concentration ([Ca²⁺]_cyt), Ca²⁺ sensitivity of contractile apparatus, and myosin light chain phosphorylation (13, 17, 22). These observations indicate that both sensor and effector mechanisms essential for acute HPV reside in PASMC. However, some studies have suggested that not all components necessary for the development of HPV are present in PASMC but may include input from endothelial cells and fibroblasts (45).

	ROLE OF [CA2+]CYT IN PASMC CONTRACTION AND PROLIFERATION

TOP ABSTRACT ROLE OF [Ca2+]cyt IN... ROLE OF K+ CHANNELS... ROLE OF SR Ca2+... ROLE OF STORE-OPERATED Ca2+... SUMMARY AND FUTURE RESEARCH GRANTS ACKNOWLEDGMENTS REFERENCES

 
An increase in [Ca²⁺]_cyt in PASMC is a major trigger for pulmonary vasoconstriction. Acute hypoxia causes a slow graded depolarization and increase in [Ca²⁺]_cyt. Both the depolarization and Ca²⁺ increase are directly proportional to the severity of hypoxia. The biphasic rise in [Ca²⁺]_cyt is generally agreed to have two components: an initial Ca²⁺ release from intracellular stores and concurrent Ca²⁺ influx from the extracellular compartment via voltage-dependent and -independent mechanisms (14, 18). A rise in [Ca²⁺]_cyt also serves as an important stimulus for cell migration, proliferation, and gene expression (14, 18). As shown in Fig. 1, an increase in [Ca²⁺]_cyt not only causes PASMC contraction by activating myosin light chain kinase but also promotes PASMC proliferation 1) by stimulating quiescent cells to enter the cell cycle and 2) by driving proliferating cells through the cell cycle and mitosis. Intracellular Ca²⁺ also activates cytoplasmic signal transduction proteins that are directly or indirectly involved in promoting cell proliferation (Fig. 1). Therefore, central to the understanding of the development of HPV is a working knowledge of the processes that control [Ca²⁺]_cyt in PASMC and how hypoxia affects them.

View larger version (24K): [in this window] [in a new window]   Fig. 1. Role of intracellular Ca2+ in regulating pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP). A rise in cytosolic free Ca2+ concentration ([Ca2+]cyt) due to Ca2+ influx and release, by activating calmodulin (CaM) in the cytosol, triggers pulmonary artery smooth muscle cell (PASMC) contraction by activating myosin light chain (MLC) kinase (which phosphorylates MLC) and stimulates PASMC proliferation by activating cytoplasmic signal transduction proteins and by propelling cells to go through the cell cycle. The resultant vasoconstriction (due to PASMC contraction) and vascular wall thickening (due to PASMC proliferation) reduces the intraluminal diameter of pulmonary arteries, which would then increase PVR and, ultimately, augment PAP. PYK2, proline-rich tyrosine kinase; Raf1, Ras-associated factor 1; MAP kinase, mitogen-activated protein kinase.

Ca²⁺ influx through the plasma membrane involves multiple Ca²⁺-permeable channels including 1) voltage-dependent Ca²⁺ channels (VDCC), which are regulated by changes in E_m; 2) receptor-operated Ca²⁺ channels (ROC), which are activated by interaction of agonists with respective receptors and the downstream signaling proteins (e.g., diacylglycerol, IP₃, and protein kinase C); and 3) store-operated Ca²⁺ channels (SOC), which are opened by depletion of Ca²⁺ from the SR (23, 37). The excitation-contraction coupling processes in pulmonary vascular smooth muscle depend on the function of all these channels. A change in E_m, for example, is required for the electromechanical coupling that alters vascular tone by regulating the activity of VDCC, which are opened by membrane depolarization and closed by membrane hyperpolarization (23, 28). Interactions of agonists (e.g., norepinephrine, phenylephrine, serotonin, endothelin-1) with membrane receptors are required for the pharmacomechanical coupling that alters vascular tone by regulating the activity of ROC and SOC.

	ROLE OF K+ CHANNELS IN HPV

TOP ABSTRACT ROLE OF [Ca2+]cyt IN... ROLE OF K+ CHANNELS... ROLE OF SR Ca2+... ROLE OF STORE-OPERATED Ca2+... SUMMARY AND FUTURE RESEARCH GRANTS ACKNOWLEDGMENTS REFERENCES

 
As mentioned earlier, E_m regulates pulmonary vascular tone by controlling Ca²⁺ influx through VDCC in PASMC. The resting E_m is primarily determined by K⁺ permeability and K⁺ concentration gradient across the plasma membrane; therefore, the activity of K⁺ channels in the plasma membrane is a critical determinant of E_m. Inhibition of K⁺ channels causes membrane depolarization, opens VDCC, promotes Ca²⁺ influx, increases [Ca²⁺]_cyt, and triggers PASMC contraction.

In PASMC, there are at least five functionally-distinguishable K⁺ channels: 1) voltage-gated K⁺ (Kv) channels, 2) Ca²⁺-activated K⁺ (K_Ca) channels, 3) ATP-sensitive K⁺ (K_ATP) channels, 4) inward rectifier K⁺ (K_IR) channels, and 5) tandem pore domain K⁺ (K_T) channels. Although all K⁺ channels contribute to regulating E_m, Kv and K_T channels have been demonstrated to be the major K⁺ channels regulating the resting E_m in PASMC (24).

Blockade of Kv channels in PASMC with 4-aminopyridine (4-AP) causes membrane depolarization, induces Ca²⁺-dependent action potentials, increases [Ca²⁺]_cyt, and causes cell contraction (34, 56). Acute hypoxia (<3 min) significantly reduces Kv channel activity or whole-cell Kv currents [I_K(V)], and causes membrane depolarization in PASMC, but not in smooth muscle cells from systemic arteries (e.g., mesenteric and renal arteries) (57). These observations suggest that hypoxia-induced depolarization and Ca²⁺-dependent action potentials in pulmonary arteries (13) occur, at least partially, as a result of functional inhibition of Kv channels and decreased I_K(V) (26, 34, 35, 57). The early steps of HPV therefore appear to involve inhibition of I_K(V), E_m depolarization, and increased [Ca²⁺]_cyt due to Ca²⁺ influx via VDCC, which ultimately leads to pulmonary vasoconstriction.

Native Kv channels are homo- or heterotetramers composed of the pore forming -subunits and the cytoplasmic regulatory -subunits. Multiple Kv channel gene products, including homotetrameric channels of Kv1.2, Kv1.3, Kv2.1, and Kv3.1 subunits or heterotetrameric channels of Kv1.2/Kv1.5, Kv1.5/Kv1.1, and Kv3.1/Kv9.3 subunits have demonstrated sensitivity to acute hypoxia (5). Among these, the Kv1.5 -subunit has been identified as a putative component of native Kv channels in hypoxia-sensitive PASMC. A study using Kv1.5 knockout mice showed that the Kv1.5 -subunit has an important role in HPV and in the hypoxia-induced reduction of I_K(V) and membrane depolarization (3). A more recent study also demonstrated that in vitro transfer of the Kv1.5 gene inhibited pulmonary arterial hypertension and restored HPV in chronically hypoxic rats (36). Although acute hypoxia reduces I_K(V) by inhibiting Kv channel function, chronic exposure to hypoxia causes sustained reduction of I_K(V) by downregulating Kv channel gene expression (19, 31, 36, 43, 44, 47).

How acute hypoxia inhibits Kv channel function and how chronic hypoxia downregulates Kv channel gene expression remain unclear. The potential intermediates or mechanisms involved in hypoxia-mediated inhibition of Kv channel function and expression include oxygen radicals, mitochondrial electron chain transport, NADPH oxidase, redox status, metabolic inhibition, cytochrome P-450 oxidoreductase, cytochrome c, cellular redox status changes, endothelin-1 production, and conformational changes of - and -subunits (e.g., due to cysteine reduction of the channel protein), and phosphorylation of - and -subunits (30).

In addition to Kv channels, acute hypoxia also inhibits K_T (12, 27) and K_Ca (16, 29) channels in PASMC. The resultant membrane depolarization or inhibition of membrane repolarization would further enhance the activity of VDCC and increase [Ca²⁺]_cyt and ultimately would sustain the acute HPV. A direct augmenting effect of acute hypoxia on VDCC has also been demonstrated in PASMC from small pulmonary arteries (10). In summary, one of the important mechanisms of acute HPV seems to be the inhibition of Kv channels (and other types of K⁺ channels to a lesser extent), which causes membrane depolarization, promotes Ca²⁺ influx via VDCC, increases [Ca²⁺]_cyt, and triggers pulmonary vasoconstriction (Fig. 2). Chronic hypoxia, in addition to attenuation of Kv channel function, also downregulates Kv channel -subunit expression. The chronic hypoxia-mediated inhibition of Kv channel expression not only contributes to PASMC contraction but may also contribute to PASMC proliferation and inhibition of PASMC apoptosis by sustained increase in [Ca²⁺]_cyt and by attenuated apoptotic volume decrease and/or cytoplasmic caspase activity, respectively (39).

View larger version (65K): [in this window] [in a new window]   Fig. 2. Roles of multiple ion channels in acute hypoxia-induced pulmonary vasoconstriction (HPV) and chronic hypoxia-induced pulmonary vascular remodeling. Acute hypoxia increases [Ca2+]cyt in PASMC by 1) inhibiting voltage-gated K+ (Kv) and tandem pore domain K+ (KT) channels and causing membrane potential (Em) depolarization, 2) directly activating voltage-dependent Ca2+ channels (VDCC), 3) activating inositol-1,4,5-triphosphate receptor (IP3-R) and ryanodine receptors (RyR) in the sarcoplasmic reticulum (SR) and inducing Ca2+ release, 4) indirectly activating store-operated Ca2+ channels (SOC) and inducing capacitative Ca2+ entry (CCE) by depleting Ca2+ from the SR, and 5) indirectly opening Ca2+-activated Cl– (ClCa) channels (due to released Ca2+) and inducing Em depolarization. The hypoxia-induced rise in [Ca2+]cyt then triggers PASMC contraction. Chronic hypoxia downregulates Kv channel expression and upregulates canonical transient receptor potential (TRPC) channel expression in PASMC. The resultant decrease in Kv currents causes Em depolarization, opens VDCC, and increases [Ca2+]cyt, whereas the increase in SOC activity enhances voltage-independent CCE and raises [Ca2+]cyt, ultimately causing sustained pulmonary vasoconstriction and stimulating PASMC proliferation. Chronic hypoxia also upregulates TRPC channel expression, enhances CCE, increases [Ca2+]cyt, and enhances AP-1 transcription factor binding activity in pulmonary artery endothelial cells (PAEC). The subsequent expression and release of vasoconstrictors [e.g., endothelin-1 (ET-1)] and growth factors (e.g., PDGF) cause PASMC contraction and proliferation via paracrine mechanisms. DAG, diacylglycerol; GPCR, G protein-coupled receptor; RTK, receptor tyrosine kinase; AP-1, activating protein 1 transcription factors; KCa, Ca2+-activated K+ channels; ROC, receptor-operated Ca2+ channels.

In addition to regional diversity, it is also becoming apparent that there is a difference in the hypoxic response due to K⁺ channels as PASMC mature from fetal to neonatal and adult PASMC (52). In fetal PASMC, resting E_m is inhibited by charybdotoxin (but not by 4-AP), I_K is inhibited more by Ca²⁺ chelation than by 4-AP, and acute hypoxia and NO can increase I_K (6, 38). This suggests that K_Ca channel activity, primarily in the form of spontaneous transient outward currents (STOCs), is prominent in hypoxia-induced fetal pulmonary vasodilation. However, in adult PASMC, E_m is modulated by and acute hypoxia partially inhibits 4-AP-sensitive I_K(V) to cause pulmonary vasoconstriction (2, 38, 57). This suggests a maturational shift in ion channel expression, which could account for differential responses to acute hypoxia as well as to vasodilators such as NO.

	ROLE OF SR CA2+ RELEASE IN HPV

TOP ABSTRACT ROLE OF [Ca2+]cyt IN... ROLE OF K+ CHANNELS... ROLE OF SR Ca2+... ROLE OF STORE-OPERATED Ca2+... SUMMARY AND FUTURE RESEARCH GRANTS ACKNOWLEDGMENTS REFERENCES

 
In addition to mediating Ca²⁺ influx in PASMC, acute hypoxia causes Ca²⁺ release by activating IP₃ receptors (IP₃-R) and RyR, also referred to as Ca²⁺ release channels, in the SR membrane (Fig. 2) (8, 21, 42, 51). Because of the limited quantity of free Ca²⁺ in the SR, the rise in [Ca²⁺]_cyt due to Ca²⁺ release is often transient. Therefore, the hypoxia-induced Ca²⁺ mobilization may be sufficient to trigger, but inadequate to maintain, PASMC contraction. In other words, both Ca²⁺ release and influx are required to induce the sustained rise in [Ca²⁺]_cyt necessary to cause HPV.

There are several potential mechanisms by which hypoxia-induced Ca²⁺ mobilization causes Ca²⁺ influx (Fig. 2): 1) the local rise in [Ca²⁺]_cyt due to Ca²⁺ release may open Ca²⁺-activated Cl^– (Cl_Ca) channels, causing E_m depolarization, and subsequently activating VDCC (40, 50, 55); and 2) depletion or emptying of Ca²⁺ from the SR triggers capacitative Ca²⁺ entry (CCE) through SOCs (25, 41, 48). Furthermore, the hypoxia-induced Ca²⁺ release has been suggested to serve as an initial inhibitor for Kv channels (34), although hypoxia inhibits Kv channels in the absence of extracellular and intracellular Ca²⁺ (57). It is likely that acute hypoxia-mediated inhibition of Kv channels and membrane depolarization result from a Ca²⁺-independent mechanism (57). Because Ca²⁺ release due to activation of RyR and IP₃-R in the SR is linked to the activation of large-conductance K_Ca channels and induction of membrane hyperpolarization, it remains unclear whether acute hypoxia-mediated Ca²⁺ release is an initial cause for E_m depolarization in PASMC. It is thus important to investigate 1) whether hypoxia-sensitive SR pools are closely colocalized with Cl_Ca channels and/or Kv channels (e.g., in caveolae), but are functionally "dissociated" from K_Ca channels in PASMC; and 2) whether K_Ca channels in PASMC are less sensitive to hypoxia-induced Ca²⁺ release as a result of hypoxia-mediated inhibition of these K_Ca channels (16, 29).

As for the K⁺ channels, it appears that developmental regulation of ryanodine-sensitive stores may also impact the pulmonary response to HPV. Case in point, 50 µM ryanodine caused a substantial [Ca²⁺]_cyt transient in fetal, but not neonatal or juvenile, rabbit distal PASMC (32), presumably because of enhanced Ca²⁺ spark activity, that could be blocked by removal of extracellular Ca²⁺ or by iberiotoxin treatment. In the latter study, ryanodine also evoked charybdotoxin-sensitive STOCs, suggesting a link between SR Ca²⁺ release channels and K_Ca activity that may modulate pulmonary vascular tone. The enhanced Ca²⁺ spark and STOC activity in fetal PASMC would therefore favor membrane hyperpolarization in these cells, leading to hypoxia-induced pulmonary vasodilation in the fetus (33).

	ROLE OF STORE-OPERATED CA2+ INFLUX IN ACUTE HPV AND CHRONIC HYPOXIA-INDUCED PAH

TOP ABSTRACT ROLE OF [Ca2+]cyt IN... ROLE OF K+ CHANNELS... ROLE OF SR Ca2+... ROLE OF STORE-OPERATED Ca2+... SUMMARY AND FUTURE RESEARCH GRANTS ACKNOWLEDGMENTS REFERENCES

 
A nifedipine- and voltage-insensitive, but SK&F 96365- and La³⁺-sensitive, Ca²⁺ entry pathway is active during hypoxia (41, 42). Activation of this pathway seems to be related to hypoxia-induced Ca²⁺ mobilization from IP₃ and/or ryanodine-sensitive SR pools. Although Ca²⁺-induced Ca²⁺ influx through sarcolemmal Ca²⁺ channels may be involved, the store depletion-mediated Ca²⁺ entry (i.e., CCE) via voltage-independent SOC has been implicated as an additional contributor to the rise in [Ca²⁺]_cyt and pulmonary vasoconstriction in response to hypoxia (41).

Current lines of thinking state that functional SOC are formed by transient receptor potential (TRP) cation channels (28). Although some TRP channel isoforms are highly expressed in animal and human PASMC (11, 48), the nature of the TRP proteins involved in forming functional SOC and the precise contribution of specific TRP channels to acute HPV and chronic hypoxia-mediated PAH are still incompletely understood. Recent studies in rat PASMC have shown that the acute hypoxia-mediated Ca²⁺ release was associated with a rise in [Ca²⁺]_cyt due to CCE; the hypoxia-mediated CCE was sensitive to SK&F 96365, Ni²⁺, and La³⁺ (49). This study provides compelling evidence that acute hypoxia-mediated Ca²⁺ release and store depletion serve as triggers to activate SOC and induce CCE. Heterogeneity of HPV (7) as well as heterogeneity of PASMC in response to acute and chronic hypoxia (45, 52) has been well demonstrated in humans and animals. It is thus possible that different PASMC (e.g., in different branches of the pulmonary arterial tree) may use different mechanisms to induce (and maintain) the rise in [Ca²⁺]_cyt.

In addition to the contribution to acute HPV, CCE and SOC TRP channels in PASMC and pulmonary artery endothelial cells (PAEC) have also been demonstrated to contribute to chronic hypoxia-mediated pulmonary vascular remodeling and sustained pulmonary vasoconstriction. Under normoxic conditions, proliferating PASMC exhibit both increased CCE and upregulated TRP channel expression relative to growth-arrested PASMC, suggesting that enhanced SOC activity may be important in mediating pulmonary vascular medial hypertrophy (11, 46, 53). Chronic exposure to hypoxia significantly upregulated canonical TRP (TRPC) channels in PASMC (49) and PAEC (9). In addition, enhanced SOC activity and CCE contribute to the increased tension observed in chronically hypoxic PASMC (15, 49). The hypoxia-mediated TRPC upregulation in PASMC may contribute to PASMC contraction and proliferation by enhancing receptor- or store-operated Ca²⁺ entry and elevating cytoplasmic and nuclear [Ca²⁺]. The hypoxia-mediated TRPC (e.g., TRPC4) upregulation in PAEC enhances amplitude of CCE and SOC currents and increases activating protein 1 transcription factor binding activity (9). Because AP-1 binding sites are present in the promoter region of many genes that are involved in stimulating PASMC proliferation, hypoxia-mediated enhancement of AP-1 binding activity would potentially stimulate synthesis of pulmonary vascular endothelium-derived vasoconstrictors and mitogens, such as PDGF, endothelin-1, and VEGF. These factors may then stimulate PASMC contraction and proliferation via paracrine binding to their receptors in PASMC (Fig. 2).

	SUMMARY AND FUTURE RESEARCH

TOP ABSTRACT ROLE OF [Ca2+]cyt IN... ROLE OF K+ CHANNELS... ROLE OF SR Ca2+... ROLE OF STORE-OPERATED Ca2+... SUMMARY AND FUTURE RESEARCH GRANTS ACKNOWLEDGMENTS REFERENCES

 
There is now good evidence to indicate that acute HPV and chronic hypoxia-induced PAH are multifactorial processes involving 1) various ion channels and 2) interactions between PASMC and PAEC. Smooth muscle cells contain sensors and effectors that respond to hypoxia. Although they were not discussed in the context of this review, endothelial cells also play a critical role in the development of sustained HPV and vascular structural changes via release of vasoconstrictors and mitogens that may increase [Ca²⁺]_cyt, increase Ca²⁺ sensitivity of smooth muscle myofilaments, and stimulate PASMC proliferation and migration. Although oxygen-sensing mechanism in PASMC is still controversial, it is generally accepted that acute HPV is caused by a rise in [Ca²⁺]_cyt due to Ca²⁺ release and influx in PASMC. Multiple ion channels and different Ca²⁺ resources are involved in eliciting the increase in [Ca²⁺]_cyt. Furthermore, downregulated K⁺ channel expression and inhibited K⁺ channel function as well as enhanced Ca²⁺ channel activity are also involved in chronic hypoxia-mediated pulmonary vascular remodeling and sustained pulmonary vasoconstriction. A detailed discussion of the cellular and molecular mechanisms of acute HPV and chronic hypoxia-induced PAH is beyond the scope of this brief review. Readers may wish to refer to accompanying articles in this Highlighted Topics series and a recently published book, titled Hypoxic Pulmonary Vasoconstriction: Cellular and Molecular Mechanisms (54), for a more thorough overview of the topic.

It is time for all investigators to work together to figure out a potential "road map" for the mechanisms by which hypoxia causes pulmonary vasoconstriction and vascular remodeling. We believe that the map will be complex and will include multiple cell types, different vasoconstrictors and growth factors, various membrane ion channels and receptors, diverse intercellular and intracellular signal transduction proteins, and a variety of transcription factors. HPV is a critical physiological mechanism to ensure gas exchange and maximal oxygenation of blood. Redundant pathways and multiple mechanisms are likely involved in this physiological response. Persistent HPV or pulmonary vascular remodeling during chronic hypoxia causes pulmonary hypertension that may lead to right heart failure and death, such as in patients with Eisenmenger syndrome and chronic obstructive pulmonary disease. Development of therapeutic approaches targeting hypoxia-sensitive ion channels would benefit or facilitate the treatment of patients with hypoxia-associated pulmonary arterial hypertension.

	GRANTS

TOP ABSTRACT ROLE OF [Ca2+]cyt IN... ROLE OF K+ CHANNELS... ROLE OF SR Ca2+... ROLE OF STORE-OPERATED Ca2+... SUMMARY AND FUTURE RESEARCH GRANTS ACKNOWLEDGMENTS REFERENCES

 
This work is supported in part by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL-54043, HL-064945, HL-66012, HL-69758, and HL-66941).

	ACKNOWLEDGMENTS

TOP ABSTRACT ROLE OF [Ca2+]cyt IN... ROLE OF K+ CHANNELS... ROLE OF SR Ca2+... ROLE OF STORE-OPERATED Ca2+... SUMMARY AND FUTURE RESEARCH GRANTS ACKNOWLEDGMENTS REFERENCES

 
The authors thank O. Platoshyn, S. Zhang, Y. Yu, I. Fantozzi, E. E. Brevnova, M. A. Sweeney, and A. Nicholson for contribution and assistance to this work.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. X.-J. Yuan, Division of Pulmonary and Critical Care Medicine, Dept. of Medicine, Univ. of California, San Diego, 9500 Gilman Dr., MC 0725, La Jolla, CA 92093-0725 (E-mail: xiyuan{at}ucsd.edu)

	REFERENCES

TOP ABSTRACT ROLE OF [Ca2+]cyt IN... ROLE OF K+ CHANNELS... ROLE OF SR Ca2+... ROLE OF STORE-OPERATED Ca2+... SUMMARY AND FUTURE RESEARCH GRANTS ACKNOWLEDGMENTS REFERENCES

 

1. Archer SL. Diversity of phenotypes and function of vascular smooth muscle cells. J Lab Clin Med 127: 524–529, 1996.[CrossRef][ISI][Medline]
2. Archer SL, Huang JMC, Reeve HL, Hampl V, Tolarová S, Michelakis E, and Weir EK. Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia. Circ Res 78: 431–442, 1996.[Abstract/Free Full Text]
3. Archer SL, London B, Hampl V, Wu X, Nsair A, Puttagunta L, Hashimoto K, Waite RE, and Michelakis E. Impairment of hypoxic pulmonary vasoconstriction in mice lacking the voltage-gated potassium channel Kv1.5. FASEB J 15: 1801–1803, 2001.[Free Full Text]
4. Berridge MJ. Cell signalling. A tale of two messengers. Nature 365: 456–459, 1993.[CrossRef][Medline]
5. Coppock EA, Martens JR, and Tamkun MM. Molecular basis of hypoxia-induced pulmonary vasoconstriction: role of voltage-gated K⁺ channels. Am J Physiol Lung Cell Mol Physiol 281: L1–L12, 2001.[Abstract/Free Full Text]
6. Cornfield DN, Reeve HL, Tolarova S, Weir EK, and Archer S. Oxygen causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel. Proc Natl Acad Sci USA 93: 8089–8094, 1996.[Abstract/Free Full Text]
7. Dawson CA. Hypoxic pulmonary vasoconstriction: heterogeneity. In: Hypoxic Pulmonary Vasoconstriction: Cellular and Molecular Mechanisms, edited by Yuan JX-J. Boston, MA: Kluwer Academic, 2004, p. 15–33.
8. Dipp M and Evans AM. Cyclic ADP-ribose is the primary trigger for hypoxic pulmonary vasoconstriction in the rat lung in situ. Circ Res 89: 77–83, 2001.[Abstract/Free Full Text]
9. Fantozzi I, Zhang S, Platoshyn O, Remillard CV, Cowling RT, and Yuan JX-J. Hypoxia increases AP-1 binding activity by enhancing capacitative Ca²⁺ entry in human pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol 285: L1233–L1245, 2003.[Abstract/Free Full Text]
10. Franco-Obregon A and Lopez-Barneo J. Differential oxygen sensitivity of calcium channels in rabbit smooth muscle cells of conduit and resistance pulmonary arteries. J Physiol 491: 511–518, 1996.[Abstract/Free Full Text]
11. Golovina VA, Platoshyn O, Bailey CL, Wang J, Limsuwan A, Sweeney M, Rubin LJ, and Yuan JX-J. Upregulated TRP and enhanced capacitative Ca²⁺ entry in human pulmonary artery myocytes during proliferation. Am J Physiol Heart Circ Physiol 280: H746–H755, 2001.[Abstract/Free Full Text]
12. Gurney AM, Osipenko ON, MacMillan D, and Kempsill FEJ. Potassium channels underlying the resting potential of pulmonary artery smooth muscle cells. Clin Exp Pharmacol Physiol 29: 330–333, 2002.[CrossRef][ISI][Medline]
13. Harder DR, Madden JA, and Dawson C. Hypoxic induction of Ca²⁺-dependent action potentials in small pulmonary arteries of the cat. J Appl Physiol 59: 1389–1393, 1985.[Abstract/Free Full Text]
14. Hardingham GE, Chawla S, Johnson CM, and Bading H. Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385: 260–265, 1997.[CrossRef][Medline]
15. Hong ZG, Klein JJ, Nelson DP, Hong FX, Varghese A, and Weir EK. Capacitative calcium entry in pulmonary arteries increases in chronic hypoxia (Abstract). Am J Respir Crit Care Med 169: A401, 2004.
16. Lee S, Park M, So I, and Earm YE. NADH and NAD modulates Ca²⁺-activated K⁺ channels in small pulmonary arterial smooth muscle cells of the rabbit. Pflügers Arch 427: 378–380, 1994.[CrossRef][ISI][Medline]
17. Madden JA, Dawson CA, and Harder DR. Hypoxia-induced activation in small isolated pulmonary arteries from the cat. J Appl Physiol 59: 113–119, 1985.[Abstract/Free Full Text]
18. Means AR. Calcium calmodulin and cell cycle regulation. FEBS Lett 347: 1–4, 1994.[CrossRef][ISI][Medline]
19. Michelakis ED, McMurtry MS, Wu XC, Dyck JRB, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R, and Archer SL. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 105: 244–250, 2002.[Abstract/Free Full Text]
20. Michelakis ED, Reeve HL, Huang JM, Tolarova S, Nelson DP, Weir EK, and Archer SL. Potassium channel diversity in vascular smooth muscle cells. Can J Physiol Pharmacol 75: 889–897, 1997.[CrossRef][ISI][Medline]
21. Morio Y and McMurtry IF. Ca²⁺ release from ryanodine-sensitive store contributes to mechanism of hypoxic vasoconstriction in rat lungs. J Appl Physiol 92: 527–534, 2002.[Abstract/Free Full Text]
22. Murray TR, Chen L, Marshall BE, and Macarak EJ. Hypoxic contraction of cultured pulmonary vascular smooth muscle cells. Am J Respir Cell Mol Biol 3: 457–465, 1990.[ISI][Medline]
23. Nelson MT, Patlak JB, Worley JF, and Standen NB. Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone. Am J Physiol Cell Physiol 259: C3–C18, 1990.[Abstract/Free Full Text]
24. Nelson MT and Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol Cell Physiol 268: C799–C822, 1995.[Abstract/Free Full Text]
25. Ng LC and Gurney AM. Store-operated channels mediate Ca²⁺ influx and contraction in rat pulmonary artery. Circ Res 89: 923–929, 2001.[Abstract/Free Full Text]
26. Olschewski A, Hong Z, Nelson DP, and Weir EK. Graded response of K⁺ current, membrane potential, and [Ca²⁺]_i to hypoxia in pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 283: L1143–L1150, 2002.[Abstract/Free Full Text]
27. Osipenko ON, Evans AM, and Gurney AM. Regulation of the resting potential of rabbit pulmonary artery myocytes by a low threshold, O₂-sensing potassium current. Br J Pharmacol 120: 1461–1470, 1997.[CrossRef][ISI][Medline]
28. Parekh AB and Penner R. Store depletion and calcium influx. Physiol Rev 77: 901–930, 1997.[Abstract/Free Full Text]
29. Park MK, Lee SH, Lee SJ, Ho WK, and Earm YE. Different modulation of Ca-activated K channels by the intracellular redox potential in pulmonary and ear arterial smooth muscle cells of the rabbit. Pflügers Arch 430: 308–314, 1995.[CrossRef][ISI][Medline]
30. Patel H, Remillard CV, and Yuan JX-J. Hypoxic regulation of K⁺ channel expression and function in pulmonary artery smooth muscle cells. In: Hypoxic Pulmonary Vasoconstriction: Cellular and Molecular Mechanisms, edited by Yuan JX-J. Boston, MA: Kluwer Academic, 2004, p. 165–198.
31. Platoshyn O, Yu Y, Golovina VA, McDaniel SS, Krick S, Li L, Wang JY, Rubin LJ, and Yuan JX-J. Chronic hypoxia decreases K_V channel expression and function in pulmonary artery myocytes. Am J Physiol Lung Cell Mol Physiol 280: L801–L812, 2001.[Abstract/Free Full Text]
32. Porter VA, Reeve HL, and Cornfield DN. Fetal rabbit pulmonary artery smooth muscle cell response to ryanodine is developmentally regulated. Am J Physiol Lung Cell Mol Physiol 279: L751–L757, 2000.[Abstract/Free Full Text]
33. Porter VA, Rhodes MT, Reeve HL, and Cornfield DN. Oxygen-induced fetal pulmonary vasodilation is mediated by intracellular calcium activation of K_Ca channels. Am J Physiol Lung Cell Mol Physiol 281: L1379–L1385, 2001.[Abstract/Free Full Text]
34. Post JM, Gelband CH, and Hume JR. [Ca²⁺]_i inhibition of K⁺ channels in canine pulmonary artery. Novel mechanism for hypoxia-induced membrane depolarization. Circ Res 77: 131–139, 1995.[Abstract/Free Full Text]
35. Post JM, Hume JR, Archer SL, and Weir EK. Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiol Cell Physiol 262: C882–C890, 1992.[Abstract/Free Full Text]
36. Pozeg ZI, Michelakis E, McMurtry MS, Thébaud B, Wu XC, Dyck JRB, Hashimoto K, Wang S, Moudgil R, Harry G, Sultanian R, Koshal A, and Archer SL. In vivo gene transfer of the O₂-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation 107: 2037–2044, 2003.[Abstract/Free Full Text]
37. Putney JW Jr, Broad LM, Braun FJ, Lievremont JP, and Bird GS. Mechanisms of capacitative calcium entry. J Cell Sci 114: 2223–2229, 2001.[ISI][Medline]
38. Reeve HL, Weir EK, Archer SL, and Cornfield DN. A maturational shift in pulmonary K⁺ channels, from Ca²⁺ sensitive to voltage dependent. Am J Physiol Lung Cell Mol Physiol 275: L1019–L1025, 1998.[Abstract/Free Full Text]
39. Remillard CV and Yuan JX-J. Activation of K⁺ channels: an essential pathway in programmed cell death. Am J Physiol Lung Cell Mol Physiol 286: L49–L67, 2004.[Abstract/Free Full Text]
40. Remillard CV, Zhang WM, Shimoda LA, and Sham JSK. Physiological properties and functions of Ca²⁺ sparks in rat intrapulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 283: L433–L444, 2002.[Abstract/Free Full Text]
41. Robertson TP, Hague D, Aaronson PI, and Ward JPT. Voltage-independent calcium entry in hypoxic pulmonary vasoconstriction of intrapulmonary arteries of the rat. J Physiol 525: 669–680, 2000.[Abstract/Free Full Text]
42. Salvaterra CG and Goldman WF. Acute hypoxia increases cytosolic calcium in cultured pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 264: L323–L328, 1993.[Abstract/Free Full Text]
43. Shimoda LA, Sylvester JT, and Sham JSK. Chronic hypoxia alters effects of endothelin and angiotensin on K⁺ currents in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol 277: L431–L439, 1999.[Abstract/Free Full Text]
44. Smirnov SV, Robertson TP, Ward JPT, and Aaronson PI. Chronic hypoxia is associated with reduced delayed rectifier K⁺ current in rat pulmonary artery muscle cells. Am J Physiol Heart Circ Physiol 266: H365–H370, 1994.[Abstract/Free Full Text]
45. Stenmark KR and Mecham RP. Cellular and molecular mechanisms of pulmonary vascular remodeling. Annu Rev Physiol 59: 89–144, 1997.[CrossRef][ISI][Medline]
46. Sweeney M, Yu Y, Platoshyn O, Zhang S, McDaniel SS, and Yuan JX-J. Inhibition of endogenous TRP1 decreases capacitative Ca²⁺ entry and attenuates pulmonary artery smooth muscle cell proliferation. Am J Physiol Lung Cell Mol Physiol 283: L144–L155, 2002.[Abstract/Free Full Text]
47. Wang J, Juhaszova M, Rubin LJ, and Yuan XJ. Hypoxia inhibits gene expression of voltage-gated K⁺ channel a subunits in pulmonary artery smooth muscle cells. J Clin Invest 100: 2347–2353, 1997.[ISI][Medline]
48. Wang J, Shimoda LA, and Sylvester JT. Capacitative calcium entry and TRPC channel proteins are expressed in rat distal pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol 286: L848–L858, 2004.[Abstract/Free Full Text]
49. Wang J, Weigand L, Sylvester JT, and Shimoda LA. Enhanced capacitative Ca²⁺ entry (CCE) contributes to elevated resting Ca²⁺ and tension in pulmonary arterial smooth muscle from rats exposed to chronic hypoxia (CH) (Abstract). Am J Respir Crit Care Med 169: A400, 2004.
50. Wang Q, Wang YX, Yu M, and Kotlikoff MI. Ca²⁺-activated Cl^– currents are activated by metabolic inhibition in rat pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 273: C520–C530, 1997.[Abstract/Free Full Text]
51. Waypa GB, Marks JD, Mack MM, Boriboun C, Mungai PT, and Schumacker PT. Mitochondrial reactive oxygen species trigger calcium increases during hypoxia in pulmonary arterial myocytes. Circ Res 91: 719–726, 2002.[Abstract/Free Full Text]
52. Weir EK, Reeve HL, Cornfield DN, Tristani-Firouzi M, Peterson DA, and Archer SL. Diversity of response in vascular smooth muscle cells to changes in oxygen tension. Kidney Int 51: 462–466, 1997.[ISI][Medline]
53. Yu Y, Sweeney M, Zhang S, Platoshyn O, Landsberg J, Rothman A, and Yuan JX-J. PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Am J Physiol Cell Physiol 284: C316–C330, 2003.[Abstract/Free Full Text]
54. Yuan JX-J. Hypoxic Pulmonary Vasoconstriction: Cellular and Molecular Mechanisms. Boston, MA: Kluwer Academic, 2004.
55. Yuan X-J. Role of calcium-activated chloride current in regulating pulmonary vascular tone. Am J Physiol Lung Cell Mol Physiol 272: L959–L968, 1997.[Abstract/Free Full Text]
56. Yuan X-J. Voltage-gated K⁺ currents regulate resting membrane potential and [Ca²⁺]_i in pulmonary arterial myocytes. Circ Res 77: 370–378, 1995.[Abstract/Free Full Text]
57. Yuan X-J, Goldman WF, Tod ML, Rubin LJ, and Blaustein MP. Hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes. Am J Physiol Lung Cell Mol Physiol 264: L116–L123, 1993.[Abstract/Free Full Text]

This article has been cited by other articles:

				A. L. Firth, K. H. Yuill, and S. V. Smirnov Mitochondria-dependent regulation of Kv currents in rat pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L61 - L70. [Abstract] [Full Text] [PDF]

				L. E. Fredenburgh, O. D. Liang, A. A. Macias, T. R. Polte, X. Liu, D. F. Riascos, S. W. Chung, S. L. Schissel, D. E. Ingber, S. A. Mitsialis, et al. Absence of Cyclooxygenase-2 Exacerbates Hypoxia-Induced Pulmonary Hypertension and Enhances Contractility of Vascular Smooth Muscle Cells Circulation, April 22, 2008; 117(16): 2114 - 2122. [Abstract] [Full Text] [PDF]

				O. Platoshyn, Y. Yu, E. A Ko, C. V. Remillard, and J. X.-J. Yuan Heterogeneity of hypoxia-mediated decrease in IK(V) and increase in [Ca2+]cyt in pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L402 - L416. [Abstract] [Full Text] [PDF]

				G. Zhao, A. Adebiyi, Q. Xi, and J. H. Jaggar Hypoxia reduces KCa channel activity by inducing Ca2+ spark uncoupling in cerebral artery smooth muscle cells Am J Physiol Cell Physiol, June 1, 2007; 292(6): C2122 - C2128. [Abstract] [Full Text] [PDF]

				G. Y. Rochefort and E. D. Michelakis COUNTERPOINT: RELEASE OF AN ENDOTHELIUM-DERIVED VASOCONSTRICTOR AND RHOA/RHO KINASE-MEDIATED CALCIUM SENSITIZATION OF SMOOTH MUSCLE CELL CONTRACTION ARE NOT THE MAIN EFFECTORS FOR FULL AND SUSTAINED HPV J Appl Physiol, May 1, 2007; 102(5): 2072 - 2075. [Full Text] [PDF]

				C. D. Fike, M. R. Kaplowitz, Y. Zhang, and J. A. Madden Voltage-gated K+ channels at an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets Am J Physiol Lung Cell Mol Physiol, December 1, 2006; 291(6): L1169 - L1176. [Abstract] [Full Text] [PDF]

				K. R. Stenmark, K. A. Fagan, and M. G. Frid Hypoxia-Induced Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms Circ. Res., September 29, 2006; 99(7): 675 - 691. [Abstract] [Full Text] [PDF]

				O. Platoshyn, E. E. Brevnova, E. D. Burg, Y. Yu, C. V. Remillard, and J. X.-J. Yuan Acute hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells Am J Physiol Cell Physiol, March 1, 2006; 290(3): C907 - C916. [Abstract] [Full Text] [PDF]

				P. I. Aaronson, T. P. Robertson, G. A. Knock, S. Becker, T. H. Lewis, V. Snetkov, and J. P. T. Ward Hypoxic pulmonary vasoconstriction: mechanisms and controversies J. Physiol., January 1, 2006; 570(1): 53 - 58. [Abstract] [Full Text] [PDF]

				M. S. Wolin, M. Ahmad, and S. A. Gupte Oxidant and redox signaling in vascular oxygen sensing mechanisms: basic concepts, current controversies, and potential importance of cytosolic NADPH Am J Physiol Lung Cell Mol Physiol, August 1, 2005; 289(2): L159 - L173. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (20) Citing Articles via Google Scholar Google Scholar Articles by Mauban, J. R. H. Articles by Yuan, J. X.-J. Search for Related Content PubMed PubMed Citation Articles by Mauban, J. R. H. Articles by Yuan, J. X.-J.