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J Appl Physiol 100: 318-327, 2006; doi:10.1152/japplphysiol.00937.2005
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INVITED REVIEW

HIGHLIGHTED TOPICS
Regulation of Cerebral Circulation

Endothelial influences on cerebrovascular tone

Jon Andresen,1 Nadeem I. Shafi,2 and Robert M. Bryan, Jr.1

1Department of Anesthesiology, and 2Section of Pediatric Critical Care, Baylor College of Medicine, Houston, Texas


   ABSTRACT
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The cerebrovascular endothelium exerts a profound influence on cerebral vessels and cerebral blood flow. This review summarizes current knowledge of various dilator and constrictor mechanisms intrinsic to the cerebrovascular endothelium. The endothelium contributes to the resting tone of cerebral arteries and arterioles by tonically releasing nitric oxide (NO{bullet}). Dilations can occur by stimulated release of NO{bullet}, endothelium-derived hyperpolarization factor, or prostanoids. During pathological conditions, the dilator influence of the endothelium can turn to that of constriction by a variety of mechanisms, including decreased NO{bullet} bioavailability and release of endothelin-1. The endothelium may participate in neurovascular coupling by conducting local dilations to upstream arteries. Further study of the cerebrovascular endothelium is critical for understanding the pathogenesis of a number of pathological conditions, including stroke, traumatic brain injury, and subarachnoid hemorrhage.

endothelium; cerebral vessels; endothelium-derived hyperpolarization factor; nitric oxide; conducted dilation

MICROSCOPIC INVESTIGATIONS of brain capillaries provided the first description of endothelial cells in 1845, although they were not named until 1872 (76). For over 100 years thereafter, endothelial cells were largely regarded as the inactive lining of blood vessels and the inert walls of capillaries. Today, the endothelium has become a major focus of cardiovascular research.

The study of endothelial cells increased following the identification of nitric oxide (NO{bullet}) as the endothelium-derived relaxing factor in the 1980s (69, 70, 101, 136, 148, 184). We now know that the endothelium is a regulator of vasculogenesis, vascular tone, inflammation, and thrombosis (19, 39, 62, 179). Uniquely, cerebral endothelial cells form tight junctions, establishing the blood-brain barrier (72). Endothelial dysfunction is an important factor in the pathogenesis of cardiovascular diseases such as atherosclerosis, stroke, diabetes, subarachnoid hemorrhage, and hypertension (29, 49, 60, 62, 95, 111, 129, 177). Cerebral blood vessels are also being increasingly investigated for their role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (93).

Many substances, including acetylcholine, bradykinin, ATP, and ADP, dilate cerebral blood vessels by activating G-protein-coupled receptors located on the endothelium (13, 193, 199–201). These dilations proceed via production of NO{bullet}, certain prostanoids, and/or endothelium-derived hyperpolarization factor (EDHF). The endothelium can also release factors that constrict cerebral vessels such as endothelin-1 (ET-1). Figure 1 summarizes the dilator and constrictor effects of endothelium on cerebral vessels.



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  		Fig. 1. The endothelium generates a variety of signals that influence cerebrovascular tone under normal conditions and during disease. Dilators include nitric oxide (NO{bullet}), endothelium-derived hyperpolarization factor (EDHF), prostacyclin (PGI2), and prostaglandin E2 (PGE2). Under normal conditions, release of NO{bullet} probably predominates in large cerebral arteries, whereas EDHF may become more important in smaller arteries and arterioles. Endothelium-derived PGI2 probably does not significantly contribute to resting cerebrovascular tone in adults under normal conditions, although PGI2 is important during development. Endothelium-derived constrictors include endothelin (ET)-1, thromboxane A2 (TXA2), and prostaglandin F2{alpha} (PGF2{alpha}). Like PGI2, these agents probably do not normally contribute to cerebrovascular tone in adults, although they may become important in pathological conditions.

 
Investigation of the cerebral endothelium has traditionally lagged behind that of endothelium from more accessible peripheral vessels despite its importance in cerebrovascular regulation. In this review, we discuss current knowledge of endothelium-derived factors and processes that directly influence cerebrovascular tone.


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Nitric oxide.   Nitric oxide synthase (NOS) is responsible for the O2-dependent conversion of L-arginine to NO{bullet} and L-citrulline (66). There are three isoforms of NOS: neuronal (nNOS or NOS1), inducible (iNOS or NOS2), and endothelial (eNOS or NOS3). Under normal conditions, nNOS and eNOS are found in neurons and cerebral vessels, respectively (18, 20, 66). Although iNOS is not normally expressed in the brain, a large number of stimuli and pathological conditions such as lipopolysaccharide exposure and hypertension can induce its expression in neurons and in blood vessels (5, 23, 90).

Under basal conditions, tonic release of NO{bullet} is a significant regulator of resting cerebral blood flow (Fig. 1). Accordingly, NOS inhibition constricts cerebral arteries both in vitro and in vivo and decreases cerebral blood flow (59, 73, 159, 200, 201). eNOS is an important source of the NO{bullet} that contributes to the basal tone of cerebral arteries (12, 159, 178, 186). Additionally, NO{bullet} derived from nNOS located in parenchymal neurons or perivascular nerves dilates cerebral arteries (1, 83, 99, 100, 120, 138, 196). Although NO{bullet} is an important regulator of the cerebral circulation, the relative importance of eNOS vs. nNOS in the control of cerebral blood flow is not known.

NO{bullet} generated by eNOS diffuses from the endothelium to the smooth muscle where it binds to and activates soluble guanylate cyclase, resulting in increased levels of cyclic guanine monophosphate (141). Cyclic guanine monophosphate activates protein kinase G, causing relaxation of smooth muscle by opening K+ channels and/or by reducing the sensitivity of the contractile machinery to Ca2+ (63, 118). Generally, this pathway is considered the predominant mechanism for NO{bullet}-mediated dilations of cerebral arteries and arterioles (24, 63, 171). A supplemental mechanism has also been proposed in cerebral arteries in which NO{bullet} inhibits the synthesis of the constrictor eicosanoid, 20-HETE, although relatively high concentrations of NO{bullet} may be required (4, 175).

In endothelial cells, eNOS is primarily localized to caveolae found in the plasma membrane (65, 165). The major scaffolding protein in caveolae is caveolin-1 (cav-1) (79), and binding of eNOS to cav-1 inhibits NO{bullet} production (71, 78, 102). Localization of eNOS to caveolae may be critical for its regulation. For example, in angiotensin-induced hypertension, eNOS is primarily located in the golgi apparatus, resulting in decreased agonist-induced NO{bullet} production (77).

The regulation of eNOS is multifaceted. Calcium is an important regulator of eNOS, and many agonists activate eNOS by increasing intracellular Ca2+ (160). Calcium complexes with calmodulin and activates eNOS by displacing it from cav-1 (133, 134). Additionally, eNOS in cerebral arteries and arterioles appears to be directly regulated by heat shock protein (HSP90), serine/threonine phosphorylation, and tyrosine phosphorylation.

HSP90 and eNOS colocalize within endothelial cells (106). Geldanamycin, an inhibitor of HSP90, reduces cyclic guanine monophosphate levels and constricts cerebral arteries to a similar extent as NOS inhibition (106). Thus HSP90 may contribute to the regulation of basal NO{bullet} production. Studies of cerebral arterioles in vivo demonstrate that agonist-induced NO{bullet} production may or may not involve HSP90. For example, dilation to acetylcholine, but not to ADP, is attenuated following inhibition of HSP90 (189).

In cerebral arteries, endothelium-dependent vasodilation to acetylcholine is sensitive to NOS inhibition and is mediated by M5 muscarinic receptors (193). In addition, acetylcholine-induced dilations in basilar arteries and pial arterioles in vivo are attenuated following inhibition of tyrosine kinase or phosphatidylinositol-3-kinase (PI3-kinase) (110, 112, 189). It is not known if HSP90, tyrosine kinase, and PI3-kinase are part of the same pathway or if they represent unique pathways in the regulation of eNOS. It is known, however, that PI3-kinase activates the serine/threonine kinase Akt (44, 51, 113). In turn, Akt phosphorylates eNOS, enhancing its sensitivity to Ca2+/calmodulin (52, 68).

Estrogen enhances basal and agonist-induced NO{bullet} production through regulation of eNOS expression and activity (74, 152). Estrogen increases eNOS expression while decreasing that of cav-1, resulting in enhanced eNOS activity (130, 152, 191). Additionally, estrogen both rapidly activates and chronically upregulates the PI3-kinase-Akt-eNOS pathway in cerebral vessels (173). Thus estrogen significantly affects the production of NO{bullet} by targeting several control sites for eNOS regulation and expression.

The NO{bullet} system is altered in many pathological states. Endothelial cells, neurons, glia, and invading leukocytes all produce reactive oxygen species, which can scavenge NO{bullet}, cause endothelial-dysfunction, and alter vascular tone (47, 167, 174). For example, superoxide (O2{bullet}–) mediates the endothelial dysfunction observed in the pial arteries of hyperhomocysteinemic mice (45). Ironically, under conditions of limited substrate availability, the conversion of L-arginine to L-citrulline by eNOS can become uncoupled from NO{bullet} production, resulting in the production of O2{bullet}– instead of NO{bullet} (105, 140). After brain injury, both L-arginine and tetrahydrobiopterin (a necessary NOS cofactor) may become depleted. L-arginine infusion after brain injury improves cerebral blood flow and neurological outcome, suggesting that eNOS is substrate and/or cofactor limited in this setting (37, 192).

The reaction of O2{bullet}– with NO{bullet} forms the potent oxidant, peroxynitrite. Beyond reducing NO{bullet} bioavailability, formation of peroxynitrite can exacerbate oxidative stress by inhibiting manganese superoxide O2{bullet}– dismutase, resulting in reduced antioxidant capacity (87, 121, 158, 183). Oxidative stress due to formation of reactive species such as O2{bullet}– and peroxynitrite mediates the damage caused by both brain trauma and ischemia/reperfusion injury (14, 88, 187).

"Statins" (3-hydroxy-3-methylglutaryl-CoA or HMG-CoA reductase) inhibitors reduce serum cholesterol and lower the risk for cardiovascular diseases, including heart attack and stroke (55). Statins increase cerebral blood flow and improve outcome following stroke, although this may not be due to the cholesterol-lowering effects of statins because cholesterol has not been firmly established as an independent risk factor for stroke (55–57, 192). The protection against stroke by statins is, at least in part, due to increased eNOS expression (55). Statins also reduce NADPH oxidase activity, which, when combined with increased eNOS expression, results in enhanced NO{bullet} bioavailability and preservation of vascular function (185). Thus statins appear to protect the brain against stroke-induced ischemia/reperfusion injury by altering cerebrovascular function.

EDHF.   Shortly after the discovery of NO{bullet} as endothelium-derived relaxing factor, evidence emerged that there was another endothelium-dependent dilator, which became known as EDHF (Fig. 1) (26, 91, 184). EDHF-mediated dilation occurs independently of a NOS or cyclooxygenase (COX) metabolite and is characterized by endothelium-dependence, hyperpolarization of smooth muscle, and activation of K+ channels (81). EDHF may refer to a process and/or a discrete entity such as a diffusible factor.

Agonists that elicit EDHF-mediated responses, such as UTP and ATP, maximally dilate cerebral arteries in vitro after inhibition of NOS and COX (199, 200). In the rat middle cerebral artery, EDHF-mediated dilation requires increases in the endothelial Ca2+ concentration (124, 125, 202). The rise in endothelial Ca2+ is associated with endothelial hyperpolarization that is sensitive to TRAM-34, a specific blocker of intermediate conductance Ca2+-activated K+ (IKCa) channels (126). Activation of IKCa channels alone is sufficient to elicit endothelial hyperpolarization and subsequent vasodilation in cerebral arteries, and neither small nor large conductance K+ channels are involved (126, 131). In contrast, peripheral arteries require both small K channels and IKCa channels for endothelial hyperpolarization (26).

How endothelial hyperpolarization leads to subsequent hyperpolarization of smooth muscle is not clear. Recent evidence indicates that the response is not mediated by arachidonic acid metabolites or reactive oxygen species (202). There is, however, increasing evidence that EDHF-mediated dilation in peripheral and cerebral arteries may depend on myoendothelial gap junctions (84–86, 181, 190). Figure 2A depicts endothelial cells and their orientation relative to underlying smooth muscle cells. Ultrastructural analysis has revealed the presence of myoendothelial gap junctions in the rat middle cerebral artery, and inhibition of gap junctions with peptide blockers for connexin-37, -43, and -40 attenuates EDHF-mediated smooth muscle hyperpolarization and vasodilation (80, 181). Regions of closely opposed endothelial and smooth muscle cell membranes are commonly observed in cerebral arteries (Fig. 2B). Actual myoendothelial gap junctions, however, are found less frequently than these close associations or than gap junctions between adjacent endothelial cells (Fig. 2C).



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  		Fig. 2. A: whole mount of rat middle cerebral artery stained with silver nitrate to visualize cell borders. Endothelial cells, ~8 µm in width, run vertically in the image. A single endothelial cell has been highlighted to aid in visualization. Vascular smooth muscle cells (SMC) can also be visualized running horizontally across the image. The line with arrows indicates the axis of the artery. B: transmission electron micrograph of a middle cerebral artery showing an endothelial SMC association. A SMC extends a slender process through a pore in the internal elastic lamina (IEL), where it comes into close contact with an overlying endothelial cell (EC; arrow). C: transmission electron micrograph of a cross section of rat middle cerebral artery showing two adjacent endothelial cells (EC1 and EC2). The arrows outline the border between the two cells with the arrow heads marking the apical and basal extremities. Two gap junctions (1 and 2) are visible. Inset: with a higher magnification of gap junction 1, note the close approximation (~2 nm) of the outer plasma membrane of EC1 and EC2 (arrows). Arrowheads denote the distance between inner plasma membrane leaflets (20 nm). All photo micrographs are courtesy of Drs. Elke Sokoya and Alan Burns, Baylor College of Medicine, Houston, TX.

 
Another recent report suggests that increased extracellular K+ is involved in the EDHF-mediated dilation to a protease-activated receptor-2 ligand, SLIGRL (amino acid sequence), in the rat middle cerebral artery (131). K+ released during endothelial hyperpolarization by IKCa channels is thought to hyperpolarize smooth muscle cells via activation of inwardly rectifying K+ channels and Na+-K+-ATPase. In response to SLIGRL, K+ itself may act as an EDHF. The mechanisms of EDHF-mediated dilation likely vary among species and vascular beds, and possibly even among stimuli within the same vessel (26, 53). Figure 3 summarizes possible EDHF pathways in cerebral vessels.



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  		Fig. 3. EDHF-mediated dilation in cerebral arteries. Stimulation by an agonist such as UTP increases intracellular Ca2+ via activation of P2Y2 receptors. In response to the increased Ca2+, intermediate conductance Ca2+-activated K+ (IKCa) channels open and allow K+ to flow out of the cell, resulting in hyperpolarization of the endothelium. Hyperpolarization then spreads to the smooth muscle by 3 possible pathways causing vasodilation. First, the hyperpolarization may be conducted through myoendothelial gap junctions to the smooth muscle. Second, K+ released from the endothelium may activate inwardly rectifying K+ channels and the Na+-K+ase on smooth muscle. Third, an as yet unidentified diffusible factor may be released from the endothelium in response to hyperpolarization, resulting in relaxation of smooth muscle.

 
Several interesting findings demonstrate that EDHF complements endothelium-derived NO{bullet} in the control of cerebral circulation. First, EDHF becomes more important than NO{bullet} for some dilators as the diameters of cerebral vessels decrease (200). For example, dilation to luminally applied ATP in isolated penetrating arterioles is entirely due to EDHF, and no role for NO{bullet} is observed (200). The generalization that NO{bullet} becomes less important as vessel diameter decreases, however, may not hold for all agonists. For example, dilations to acetylcholine seems to be mediated exclusively by NO{bullet} in pial arterioles (62). Second, EHDF-mediated dilations are upregulated after stroke and traumatic brain injury, whereas dilations caused by endothelium-derived NO{bullet} are compromised (82, 123, 127). Thus, during pathological conditions, upregulation of EDHF may compensate for dysfunction in the NO{bullet} system to maintain cerebral blood flow (26).

The overwhelming in vitro evidence for EDHF suggests that EDHF likely has physiological significance. EDHF-mediated dilations occur in cerebral arterioles in vivo in response to ADP (191), and increases in cortical perfusion to intravenous ATP are preserved in the rat following NOS and COX inhibition (unpublished data from our laboratory). Additionally, in vivo dilations attributable to EDHF have been observed in the pial arterioles of mice deficient for eNOS (61). EDHF may contribute to resting tone since inhibition of K+ channels and gap junctions involved with EDHF-mediated responses causes constriction of cerebral arterioles in vivo (61, 190). Thus emerging evidence supports an important role for EDHF in the cerebral circulation. Understanding this role could represent a new chapter in the regulation of cerebral blood flow. Determining how pathological conditions affect EDHF should lead to interventions that preserve adequate cerebral perfusion and, therefore, neuronal viability.

Prostacyclin and other eicosanoids.   Arachidonic acid is metabolized to a number of products that are collectively called eicosanoids (19). Some eicosanoids are dilators, whereas others are constrictors. The first step in eicosanoid synthesis involves the liberation of arachidonic acid from the phospholipid membrane primarily by phospholipase A2. Once liberated, arachidonic acid can be further metabolized by COX, lipoxygenase, epoxygenase, or {Omega} hydroxylase (19). The primary pathway for arachidonic acid metabolism depends on the cell type, physiological state, and/or pathological condition.

The COX pathway was the first to be discovered and remains the best understood. Three COX isoforms are variably expressed in neurons, glia, and cerebral vessels (36, 107–109, 170). It is generally considered that COX-1 is stably and constitutively expressed in adults; however, endothelial expression can be increased by stimuli such as shear stress and estrogen (146, 147). Although it is not present in most tissues, COX-2 is normally expressed in the brain and in the piglet cerebrovascular endothelium (149, 155, 170, 194). The expression of COX-2 can be induced by inflammatory states and other conditions involving oxidative stress (22, 89, 90, 170, 194). The recently discovered COX-3 is highly expressed in the brain, primarily in cerebral vessels (36, 107–109). Interestingly, inhibition of COX-3 by acetaminophen reduces prostaglandin production in cerebrovascular endothelial cells, uncovering a previously unknown action of acetaminophen (109).

Dilator products of the COX pathway include prostacyclin (PGI2), prostaglandin E2, and prostaglandin D2. Constrictor products include prostaglandin F2{alpha} and thromboxane A2 (TXA2) (27, 170). Normally, PGI2 and prostaglandin E2 are regarded as the major endothelial COX metabolites (137). Figure 1 shows the effects of these metabolites on vascular tone.

PGI2 is the most extensively studied arachidonic acid metabolite in cerebrovascular endothelium. The COX reaction produces prostaglandin H2, which is converted to PGI2 by PGI2 synthase (143, 170). After synthesis, PGI2 diffuses to the smooth muscle, where it activates adenylate cyclase through G-protein-coupled receptors, increasing cyclic AMP and protein kinase A activity (19). The activation of protein kinase A causes K+ channels to open and produces smooth muscle hyperpolarization (150). Voltage-sensitive Ca2+ channels close, resulting in decreased Ca2+ concentration and vasodilation (21, 182). Endothelial-mediated responses in neonates primarily involve COX metabolites, although NO{bullet} becomes an increasingly important dilator during development (207). In adults, endothelial-mediated dilations are dominated by NO{bullet} and EDHF (26, 81, 200–202).

Although the lipoxygenase, epoxygenase, and {Omega} hydroxylase pathways synthesize vasoactive metabolites, these pathways are not well understood in the context of the cerebrovasculature. Products of the epoxygenase (cis-epoxyeicosatrienoic acids or EETs), and lipoxygenase pathways appear to be EDHFs in some peripheral vessels including those in the heart (30, 31, 132). Nevertheless, these pathways do not appear to be involved with EDHF-mediated dilations in the rat middle cerebral artery (202). EETs are synthesized in astrocytes and thus may be involved with the coupling of blood flow to neural activation (2, 3, 132, 153). The {Omega} hydroxylase pathway is probably not important in endothelium, although activation of this pathway in smooth muscle potently constricts cerebral vessels (75).

Generation of O2{bullet}– is a byproduct of arachidonic acid metabolism (28). Arachidonic acid-induced dilation of cerebral vessels is due, in part, to O2{bullet}– and activation of Ca2+-activated K+ channels (48, 62, 116, 172). Increased levels of O2{bullet}–, however, can result in oxidative stress if production exceeds antioxidant capacity. Oxidative stress can damage cellular components and reduce NO{bullet} bioavailability, which constricts cerebral vessels (15).

The eicosanoids prostaglandin E2, PGI2, and TXA2 become elevated in injured brain tissue within hours after injury (46, 168, 197). TXA2, in particular, may be associated with the vasoconstriction that occurs after reperfusion, since levels of TXA2 remain normal after ischemia alone but are elevated after ischemia/reperfusion (38). COX-2 is induced in the endothelium as well as in other cell types after brain injury (43, 94, 145). COX-1 may participate in minimizing post-ischemic reductions in blood flow, whereas COX-2 induction after injury appears to negatively impact tissue survival, even though some of its products may promote vasodilation (96, 97). Accordingly, eicosanoid pathways are targets in neuroprotection studies. For example, infusion of PGI2 after brain injury increases cerebral blood flow and reduces neuronal damage (16, 17, 166). Additionally, selective COX-2 inhibition reduces tissue injury and improves behavioral outcome in brain injury models (32–35).

Although there is much information regarding the COX pathway, knowledge of other arachidonic acid pathways in cerebrovascular endothelium is severely limited. A worthy goal is to elucidate the various metabolic pathways for arachidonic acid in the control of the cerebral circulation.

ET-1.   In 1988, the peptide ET-1 was characterized as an endothelium-derived constricting factor (195) (Fig. 1). Shortly thereafter, two receptors for ET-1, ETA and ETB, were found to be expressed in endothelium and smooth muscle (7, 163). ET-1 is synthesized in the endothelium from two biologically inactive precursors, preproendothelin and proendothelin (big ET-1) (135). Although its potency varies by vessel, ET-1 profoundly constricts large and small cerebral arteries, primarily via the ETA receptor subtype (58, 151, 157, 162, 203). Depending on the concentration of ET-1 and the type of cerebral vessel, ET-1 may also cause dilation via the ETB receptor subtype (176). For example, low concentrations of ET-1 dilate pial arterioles but not the basilar artery of rats (58). The dilation to ET-1 is mediated by endothelium-derived NO{bullet} (176).

Stimulation of ETA receptors on smooth muscle causes vasoconstriction by activation of several signal transduction pathways. First, ET-1 increases myosin light chain phosphorylation by elevating intracellular Ca2+ (205). The initial rise in Ca2+ is dependent on phospholipase C and 1,4,5-inositol triphosphate, which releases Ca2+ from internal stores. The sustained Ca2+ increase that follows depends on extracellular Ca2+ entry (135, 205). Second, ET-1 inhibits myosin light chain phosphatase via activation of the Rho/Rho kinase pathway (205). Third, ET-1 increases phosphorylation of thin filament-associated proteins via activation of c-Src, Janus tyrosine kinase, and protein tyrosine kinase, resulting in activation of ERK1/2 (205). Interestingly, ET-1 may also activate Cl– channels in cerebral arteries and thus may promote vasoconstriction by increasing Cl– efflux from smooth muscle cells (42).

During normal conditions, ET-1 does not appear to contribute to cerebral blood flow, suggesting that ET-1 is not normally released from cerebrovascular endothelium (114). In pathophysiological states, however, the ET-1 system is activated and may contribute to vascular dysfunction and brain injury. ET-1 synthesis increases and ET-1 receptors are upregulated in cerebral endothelial cells after ischemia/reperfusion (128, 156). Reductions in cerebral blood flow after ischemia/reperfusion and subarachnoid hemorrhage are prevented by inhibiting ET-1 receptors (161, 206). Cerebral ET-1 levels are elevated after fluid-percussion injury in piglets, leading to enhanced vasoconstriction and impaired vasodilation of pial arterioles (9, 104). The constriction may be mediated, in part, by protein kinase C-dependent suppression of ATP-sensitive K+ channel function (103). In piglets, ET-1 may also mediate the hyperoxia-induced vasoconstriction of pial arteries (8). In addition, ET-1 may contribute to the cerebrovascular endothelial dysfunction observed in diabetes. Although diabetic rats have elevated ET-1 levels, the combined ETA/ETB receptor antagonist bosentan reverses increased myogenic tone, improves endothelium-dependent vasomotion, and restores ATP-sensitive K+ channel-dependent vasodilation (54).


   POTENTIAL ROLE OF ENDOTHELIUM IN NEUROVASCULAR COUPLING
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The mechanism responsible for coupling blood flow to neural activity is an intense area of investigation. The anatomical relationship among neurons, astrocytes, and arterioles ensures that flow increases only to areas of increased activity (6). Given the mechanism as presently understood, there is little or no active participation by endothelium in the coupling of blood flow to neural activity. Nevertheless, the possibility that the endothelium participates in neuro-glio-vascular coupling has been previously proposed (64, 117, 119, 154, 169, 198, 204).

An important role for endothelium in the regulation of blood flow is to establish resting tone in cerebral vessels through basal release of NO{bullet}. In addition to setting resting cerebral blood flow, this tone acts as a background for other dilator and constrictor processes. On increased neural activity, astrocytic- and neuronally derived mediators are thought to act on smooth muscle cells to produce vasodilation or vasoconstriction (6, 93, 139, 169). This interpretation is intuitive since astrocyte foot processes and neurons are closest to smooth muscle cells (169). Mediators from neurons and/or astrocytes (ATP or ADP, for example), however, could traverse the vascular smooth muscle to stimulate receptors on the abluminal side of the endothelium. Stimulation of endothelial receptors could contribute to the neuronally mediated dilation by releasing NO{bullet}, EDHF, and/or PGI2. Although this has not been demonstrated with neural activation, dilator agents applied to the abluminal side of pial arterioles can stimulate receptors on the endothelium (50, 61, 152). Astrocytes may also elicit endothelium-dependent dilation by releasing a lipoxygenase product (142).

The increase in blood flow to a capillary bed, whether in the brain or in the periphery, requires a complex coordination of events within the vascular network. Maximizing vascular control depends not only on dilation of arterioles directly supplying the capillary bed but also on dilation of larger upstream arterioles and arteries (164). Indeed, upstream dilations of cerebral vessels occur following neural stimulation (41, 98, 144). Cerebrovascular endothelium could have a major role in mediating upstream dilations by conducting a dilator response along the vessel to upstream arteries. In support of this, local application of ATP to penetrating arterioles induces both a local vasomotor response as well as an upstream dilation (50, 92).

The obligatory role of the endothelium, which can conduct signals in excess of 1 mm, is an important aspect of the conducted vasodilator response in cerebral vessels (188). Communication between endothelial cells through gap junctions may be a mechanism for conducting vasomotor responses in cerebral arterioles and capillaries (40). Diameter changes in capillaries could be mediated by pericytes (10, 11, 180), and a dilatory signal could be conducted along the endothelium from the capillaries to upstream arterioles where further dilations would occur. Although conducted responses have not been demonstrated in cerebrovascular capillaries, they do occur in peripheral beds (115). Whether they involve capillaries or not, conducted dilations in cerebral vessels could augment neurovascular coupling.

Another mechanism for upstream dilation is important, at least in peripheral vessels. Increased blood flow increases shear stress, which mechanically deforms the endothelium and elicits dilation of upstream arterioles and arteries (115). Although flow-mediated dilation of cerebral arteries may occur (67), recent studies question a role for shear stress as a means for upstream dilation in cerebral vessels (24, 25, 122, 144).

Our understanding of how neurons, glia, and vessels interact with one another within the context of the neurovascular unit is steadily growing. Although neurons may directly alter vessel diameter in some areas of the brain, the available evidence suggests that astrocytes play a pivotal role in coupling blood flow to neural activity. Little, if any, physiological data exists for, or against, the role of the endothelium within the neurovascular unit, largely because it has not been studied. Future experiments need to be tailored to clarify the role of the endothelium in this context.


   SUMMARY
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The endothelium has an important role in the control of cerebral circulation by exerting its influence on vascular smooth muscle. This influence can be through dilator mechanisms (NO{bullet}, EDHF, and PGI2) or through constrictor mechanisms (ET-1, prostaglandin F2{alpha}, and TXA2). One promising area of research involves EDHF. We speculate that EDHF has a role equal in importance to that of endothelium-derived NO{bullet} in the control of the cerebral circulation. Nevertheless, a greater understanding of the mechanisms involved in EDHF-mediated dilations, and their roles during normal and pathological states in vivo, is required before EDHF can be raised to this level of prominence. Pathological states such as stroke, trauma, and subarachnoid hemorrhage have profound effects on the endothelium's control over vascular tone. The endothelium's dilatory role can be shifted to that of a predominantly constrictor influence during pathological states. A better understanding of vascular control during these pathological conditions should lead to therapeutic interventions that ensure sufficient cerebral blood flow to support neuronal function. Lastly, the endothelium is likely to have a major regulatory role in neurovascular coupling by mediating conducted dilations to influence local blood flow.


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This work was supported by a Bugher Foundation Award from the American Heart Association (no. 027011N) to R. M. Bryan and National Institutes of Health Grants P01 NS-38660 (to R. M. Bryan), R01 NS-46666 (to R. M. Bryan), T32 HL-07939-01A2 (to N. I. Shafi), and T32 HL-072754 and F32 HL-080916-01 (to J. Andresen).


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Andresen, Dept. of Anesthesiology, Baylor College of Medicine, One Baylor Plaza, Suite 434D, Houston, TX 77030 (e-mail: andresen@bcm.tmc.edu)


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