Functional Roles of the Rho/Rho Kinase Pathway and Protein Kinase C in the Regulation of Cerebrovascular Constriction Mediated by Hemoglobin

Wickman, Grant; Lan, Christopher Q.; Vollrath, Bozena

doi:10.1161/01.res.0000066663.12256.b2

Cited by 88 publications

(61 citation statements)

References 39 publications

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“…6A, which is published as supporting information on the PNAS web site). A previous study indicated that ␣ and ␤ are the predominant isoforms of PKC expressed in cerebral vascular smooth muscle (23). As expected, CaV1.2 protein was diffusely distributed along the surface membrane of arterial myocytes.…”

Section: Total Internal Reflection Fluorescence Microscopy (Tirf)supporting

confidence: 79%

Constitutively active L-type Ca ²⁺ channels

Navedo

Amberg

Votaw

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

195

367

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Ca 2؉ influx through L-type Ca 2؉ channels (LTCCs) influences numerous physiological processes ranging from contraction in muscle and memory in neurons to gene expression in many cell types. However, the spatiotemporal organization of functional LTCCs has been nearly impossible to investigate because of methodological limitations. Here, we examined LTCC function with high temporal and spatial resolution using evanescent field fluorescence microscopy. Surprisingly, we found that LTCCs operated in functionally organized clusters, not necessarily as individual proteins. Furthermore, LTCC function in these clusters does not appear to be controlled by simple stochastic gating but instead by a PKCdependent switch mechanism. This work suggests that resting intracellular free calcium concentration in arterial myocytes is predominantly controlled by this process in combination with rare voltage-dependent openings of individual LTCCs. We propose that Ca 2؉ influx via persistent LTCCs may be an important mechanism regulating steady-state local and global Ca 2؉ signals.evenescent field microscopy ͉ smooth muscle ͉ sparklets

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Section: Total Internal Reflection Fluorescence Microscopy (Tirf)supporting

confidence: 79%

Constitutively active L-type Ca ²⁺ channels

Navedo

Amberg

Votaw

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

195

367

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“…Relatively few studies have examined the functional importance of Rho-kinase in cerebral circulation, but recent evidence suggests that this signaling pathway mediates vasoconstrictor responses to serotonin, endothelin-1, UTP, and oxyhemoglobin (Miao et al, 2002;Nishikawa et al, 2003;Wickman et al, 2003;Luykenaar et al, 2004).…”

Section: Constrictor Responses Of Cerebral Arteries To Angiotensin IImentioning

confidence: 99%

“…Second, we examined the role of Rho-kinase in mediating vasoconstriction in response to Ang II. Activation of Rho-kinase is thought to be a key mechanism of calcium sensitization that mediates responses to several vasoconstrictors (Miao et al, 2002;Nishikawa et al, 2003;Wickman et al, 2003;Luykenaar et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Cerebral Vascular Effects of Angiotensin II: New Insights from Genetic Models

Faraci

Lamping

Modrick

et al. 2005

J Cereb Blood Flow Metab

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Very little is known regarding the mechanisms of action of angiotensin II (Ang II) or the consequences of Ang II-dependent hypertension in the cerebral circulation. We tested the hypothesis that Ang II produces constriction of cerebral arteries that is mediated by activation of AT 1A receptors and Rho-kinase. Basilar arteries (baseline diameter B130 lm) from mice were isolated, cannulated and pressurized to measure the vessel diameter. Angiotensin II was a potent constrictor in arteries from male, but not female, mice. Vasoconstriction in response to Ang II was prevented by an inhibitor of Rho-kinase (Y-27632) in control mice, and was reduced by B85% in mice deficient in expression of AT 1A receptors. We also examined the chronic effects of Ang II using a model of Ang II-dependent hypertension, mice which overexpress human renin (R þ ) and angiotensinogen (A þ ). Responses to the endothelium-dependent agonist acetylcholine were markedly impaired in R þ A þ mice (Po0.01) compared with controls, but were restored to normal by a superoxide scavenger (PEG-SOD). A-23187 (another endothelium-dependent agonist) produced vasodilation in control mice, but no response or vasoconstriction in R þ A þ mice. In contrast, dilation of the basilar artery in response to a NO donor (NONOate) was similar in R þ A þ mice and controls. Thus, Ang II produces potent constriction of cerebral arteries via activation of AT 1A receptors and Rho-kinase. There are marked gender differences in cerebral vascular responses to Ang II. Endothelial function is greatly impaired in a genetic model of Ang II-dependent hypertension via a mechanism that involves superoxide.

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“…The pathological constriction of cerebral vessels that occurs during CV may lead to ischemia, infarction or death (3,4) and the 3-10 days between the initial hemorrhage and onset of CV potentially affords the clinician a therapeutic window (5). Unfortunately, despite considerable research efforts, the etiology of CV is still unknown, and appears to be a complex combination of events (3,(6)(7)(8)(9)(10) Our research indicates that the intractable vasoconstriction seen in CV after SAH is a combination of a physiological protein kinase C-mediated contraction, followed by a pathological failure to relax, mediated by Rho-mediated inhibition of myosin light chain phosphatase (9,11). Bilirubin oxidation products (BOXes) may be responsible for one or both of these events (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

“…These increases are reported to be due to mobilization of Rho, which activates rho kinase (ROK). ROK phosphorylates and inactivates MLCP (7,(45)(46)(47). Rho is activated by a number of agonists including thromboxane A 2 and other lipid signaling molecules (48).…”

mentioning

confidence: 99%

PKC and Rho in vascular smooth muscle: Activation by BOXes and SAH CSF

Pyne‐Geithman

Nair²,

Caudell³

et al. 2008

Front Biosci

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Cerebral vasospasm (CV) remains a significant cause of delayed neurological deficit and ischemic damage after subarachnoid hemorrhage (SAH), despite intensive research effort. The current lack of an effective therapeutic approach is somewhat due to our lack of understanding regarding the mechanism by which this pathological constriction develops. Recent evidence implicates bilirubin oxidation products (BOXes) in the etiology of CV after SAH: BOXes are found in cerebrospinal fluid from SAH patients with symptomatic or angiographically visible vasospasm (CSF V ) but not in CSF from SAH patients with no vasospasm (CSF C ). We have previously published research suggesting that the etiology of CV comprises two components: a physiological stimulation to constrict and a pathological failure to relax. Both these components are elicited by CSF V , but not CSF C , and BOXes synthesized in the laboratory potentiate physiological constriction in arterial smooth muscle in vitro, and elicit contraction in pial arteries in vivo. In this paper, we will present our results concerning the action of BOXes on arterial smooth muscle constriction, compared with CSF V . We will also present evidence implicating temporal changes in PKC isoforms and Rho expression in both BOXes-and CSF V -elicited smooth muscle responses. Keywords INTRODUCTIONWorldwide, subarachnoid hemorrhage (SAH) and its sequel, cerebral vasospasm (CV), kill or seriously debilitate an estimated 1.2 million people, of both genders, and all ages and ethnic groups annually (1). In the United States alone, complications from SAH, including increased length of hospital stay, increased treatment intensity level, requirement for long-term care and intensive rehabilitation are estimated to have cost 500 million dollars in 2000 (2). The pathological constriction of cerebral vessels that occurs during CV may lead to ischemia, infarction or death (3,4) and the 3-10 days between the initial hemorrhage and onset of CV potentially affords the clinician a therapeutic window (5). Unfortunately, despite considerable research efforts, the etiology of CV is still unknown, and appears to be a complex combination of events (3,6-10) Our research indicates that the intractable vasoconstriction seen in CV after SAH is a combination of a physiological protein kinase C-mediated contraction, followed by a pathological failure to relax, mediated by Rho-mediated inhibition of myosin light chain Send correspondence to: Dr Gail Pyne-Geithman, Department of Neurology, University of Cincinnati, 2324 Vontz Center, 3125 Eden Avenue, Cincinnati, OH USA NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript phosphatase (9,11). Bilirubin oxidation products (BOXes) may be responsible for one or both of these events (12-14).The literature records a bewildering array of molecules that may be implicated in the etiology of CV after SAH. They include endothelin (15), hemoglobin (7,16), bilirubin and it's oxidation products (17-19), arachidonic acid and it's peroxidized metabolites...

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Functional Roles of the Rho/Rho Kinase Pathway and Protein Kinase C in the Regulation of Cerebrovascular Constriction Mediated by Hemoglobin

Cited by 88 publications

References 39 publications

Constitutively active L-type Ca ²⁺ channels

Constitutively active L-type Ca ²⁺ channels

Cerebral Vascular Effects of Angiotensin II: New Insights from Genetic Models

PKC and Rho in vascular smooth muscle: Activation by BOXes and SAH CSF

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Functional Roles of the Rho/Rho Kinase Pathway and Protein Kinase C in the Regulation of Cerebrovascular Constriction Mediated by Hemoglobin

Cited by 88 publications

References 39 publications

Constitutively active L-type Ca 2+ channels

Constitutively active L-type Ca 2+ channels

Cerebral Vascular Effects of Angiotensin II: New Insights from Genetic Models

PKC and Rho in vascular smooth muscle: Activation by BOXes and SAH CSF

Contact Info

Product

Resources

About

Constitutively active L-type Ca ²⁺ channels

Constitutively active L-type Ca ²⁺ channels