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 approximately 40-50% (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 approximately 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%). Lastly, SLX-2119 dilated small pial arterioles in vivo, an effect that was augmented by inhibition of NO 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.

Genetic Interference With Endothelial PPAR-γ (Peroxisome Proliferator–Activated Receptor-γ) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1–7

“…Thus, we examined effects of Y-27632, which inhibits both ROCK1 and ROCK2 isoforms equally effectively. 22 Y-27632 did not affect vascular responses in non-Tg mice, but restored endothelial function in arteries from E-V290M mice treated with Ang II (Figure 5A). …”

“…22, 23 Interactions between PPARγ, RhoA (an activator of ROCK), and ROCK has been observed in vascular muscle. 5, 6, 24 Whether similar interactions occur between PPARγ and ROCK in endothelial cells is less clear.…”

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

“…For example, isolated parenchymal arterioles develop greater myogenic tone than the middle cerebral artery. 34, 47–50 Small pial arterioles have substantial tone in vivo, 51–56 greater than that present in larger vessels within the same network. 57, 58 Through its molecular targets, eNOS influences tone in large arteries to the smallest parenchymal arterioles.…”

“…92 Activation of RhoA and its target ROCK are required for Ang II- and endothelin-1 induced endothelial dysfunction and reduced NVC (Figure 2). 50, 93 Subsequent experiments revealed that the ROCK2 isoform of ROCK was essential for Ang II-induced endothelial dysfunction. 50 …”

“…50, 93 Subsequent experiments revealed that the ROCK2 isoform of ROCK was essential for Ang II-induced endothelial dysfunction. 50 …”