title: Heterogeneous Impact of ROCK2 on Carotid and Cerebrovascular Function.
abstract: Rho kinase (ROCK) has been implicated in physiological and pathophysiological processes, including regulation of vascular function. ROCK signaling is thought to be a critical contributor to cardiovascular disease, including hypertension and effects of angiotensin II (Ang II). Two isoforms of ROCK (1 and 2) have been identified and are expressed in vascular cells. In this study, we examined the importance of ROCK2 in relation to vessel function using several models and a novel inhibitor of ROCK2. First, incubation of carotid arteries with the direct RhoA activator CN-03 or Ang II impaired endothelium-dependent relaxation by ≈40% to 50% (P<0.05) without altering endothelium-independent relaxation. Both CN-03- and Ang II-induced endothelial dysfunction was prevented by Y-27632 (an inhibitor of both ROCK isoforms) or the selective ROCK2 inhibitor SLX-2119. In contrast, SLX-2119 had little effect on contraction of carotid arteries to receptor-mediated agonists (serotonin, phenylephrine, vasopressin, or U46619). Second, in basilar arteries, SLX-2119 inhibited constriction to Ang II by ≈90% without significantly affecting responses to serotonin or KCl. Third, in isolated pressurized brain parenchymal arterioles, SLX-2119 inhibited myogenic tone in a concentration-dependent manner (eg, 1 μmol/L SLX-2119 dilated by 79±4%). Finally, SLX-2119 dilated small pial arterioles in vivo, an effect that was augmented by inhibition of nitric oxide synthase. These findings suggest that ROCK2 has major, but heterogeneous, effects on function of endothelium and vascular muscle. The data support the concept that aberrant ROCK2 signaling may be a key contributor to select aspects of large and small vessel disease, including Ang II-induced endothelial dysfunction.
authors.affiliation: From the Departments of Internal Medicine (T.M.D.S., D.A.K., M.L.M., L.D.R., F.M.F.) and Pharmacology (F.M.F.), Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine; Iowa City Veterans Affairs Healthcare System (F.M.F.); and Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Australia (T.M.D.S.).
authors.forename: T Michael
authors.initials: TM
authors.lastname: De Silva
authors.affiliation: From the Departments of Internal Medicine (T.M.D.S., D.A.K., M.L.M., L.D.R., F.M.F.) and Pharmacology (F.M.F.), Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine; Iowa City Veterans Affairs Healthcare System (F.M.F.); and Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Australia (T.M.D.S.).
authors.forename: Dale A
authors.initials: DA
authors.lastname: Kinzenbaw
authors.affiliation: From the Departments of Internal Medicine (T.M.D.S., D.A.K., M.L.M., L.D.R., F.M.F.) and Pharmacology (F.M.F.), Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine; Iowa City Veterans Affairs Healthcare System (F.M.F.); and Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Australia (T.M.D.S.).
authors.forename: Mary L
authors.initials: ML
authors.lastname: Modrick
authors.affiliation: From the Departments of Internal Medicine (T.M.D.S., D.A.K., M.L.M., L.D.R., F.M.F.) and Pharmacology (F.M.F.), Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine; Iowa City Veterans Affairs Healthcare System (F.M.F.); and Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Australia (T.M.D.S.).
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Reinhardt
authors.affiliation: From the Departments of Internal Medicine (T.M.D.S., D.A.K., M.L.M., L.D.R., F.M.F.) and Pharmacology (F.M.F.), Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine; Iowa City Veterans Affairs Healthcare System (F.M.F.); and Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Australia (T.M.D.S.). frank-faraci@uiowa.edu.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Faraci
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009599:Nitroprusside / Q000494:pharmacology; D011897:Random Allocation; D012016:Reference Values; D014661:Vasoconstriction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000804:Angiotensin II; D009599:Nitroprusside; D054460:rho-Associated Kinases; D000109:Acetylcholine
keywords: Rho kinase; angiotensin II; cerebral circulation; endothelium; myogenic tone; nitric oxide; parenchymal arterioles