Heterogeneous Impact of ROCK2 on Carotid and Cerebrovascular Function

T Michael De Silva; Dale A Kinzenbaw; Mary L Modrick; Lindsey D Reinhardt; Frank M Faraci

doi:10.1161/HYPERTENSIONAHA.116.07430

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Heterogeneous Impact of ROCK2 on Carotid and Cerebrovascular Function

Journal article

Open access

Peer reviewed

Heterogeneous Impact of ROCK2 on Carotid and Cerebrovascular Function

T Michael De Silva, Dale A Kinzenbaw, Mary L Modrick, Lindsey D Reinhardt and Frank M Faraci

Hypertension (Dallas, Tex. 1979), Vol.68(3), pp.809-817

09/2016

DOI: 10.1161/HYPERTENSIONAHA.116.07430

PMCID: PMC4982851

PMID: 27432870

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https://doi.org/10.1161/HYPERTENSIONAHA.116.07430View

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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.

Carotid Arteries - drug effects

Carotid Arteries - metabolism

Angiotensin II - pharmacology

Acetylcholine - pharmacology

Mice, Inbred C57BL

rho-Associated Kinases - genetics

Endothelium, Vascular - drug effects

Male

Reference Values

Nitroprusside - pharmacology

Random Allocation

Vasoconstriction - drug effects

Hypertension - physiopathology

Hypertension - metabolism

Cerebral Arteries - drug effects

Animals

Analysis of Variance

rho-Associated Kinases - metabolism

Cerebral Arteries - metabolism

Endothelium, Vascular - metabolism

Mice

Disease Models, Animal

Details

Title: Subtitle: Heterogeneous Impact of ROCK2 on Carotid and Cerebrovascular Function
Creators: T Michael De Silva - University of Iowa
Dale A Kinzenbaw - University of Iowa
Mary L Modrick - University of Iowa
Lindsey D Reinhardt - University of Iowa
Frank M Faraci - University of Iowa
Resource Type: Journal article
Publication Details: Hypertension (Dallas, Tex. 1979), Vol.68(3), pp.809-817
Publisher: United States
DOI: 10.1161/HYPERTENSIONAHA.116.07430
PMID: 27432870
PMCID: PMC4982851
ISSN: 0194-911X
eISSN: 1524-4563
Grant note: P01 HL062984 / NHLBI NIH HHS I01 BX001399 / BLRD VA R01 HL113863 / NHLBI NIH HHS R01 NS096465 / NINDS NIH HHS
Language: English
Date published: 09/2016
Academic Unit: Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040579902771

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