RhoA/Rho-kinase, vascular changes, and hypertension

Abstract

Hypertension, the result of a sustained increase in vascular peripheral resistance, is partly due to vascular remodeling and increased vasoconstrictor sensitivity. Stimulation of heterotrimeric G-protein-coupled receptors by various contractile agonists activates intracellular signaling molecules to result in an increase in cytosolic Ca++ and the subsequent phosphorylation of myosin light chain by Ca++/calmodulin-dependent myosin light chain kinase. Additionally, a portion of alpha-adrenergic, serotonergic, and endothelin-1-induced contraction is partially mediated by the calcium-independent activation of the small G-protein RhoA and of a downstream target, Rho-kinase. Isolated arteries from hypertensive animals have been shown to have an increased contractile sensitivity to various agonists and to exhibit evidence of remodeling. Recent data suggest that some of these vascular changes may be mediated by increased activity of RhoA/Rho-kinase, potentially introducing a novel therapeutic approach for the treatment of hypertension.

Decreased penile erection in DOCA-salt and stroke prone-spontaneously hypertensive rats

“…Additionally, data from our lab and others suggest an increase in Rho-kinase activity in the vasculature of various hypertensive animal models. 1,[23][24][25] We hypothesized, therefore, that an increase in cavernosal Rho-kinase activity contributes to the erectile dysfunction seen in DOCA and SHRSP. Intracavernosal injection of the selective inhibitor of Rho-kinase 23,31 Y-27632 (50 nmol), resulted in an increase in ICP=MAP, however this effect was significantly suppressed in the hypertensive rats ( Figure 2).…”

“…[1][2][3] The pathological changes resulting from altered vascular functioning include injury to the brain, kidney and heart. Various studies have established a clinical correlation between incidence of hypertension and erectile dysfunction.…”

“…1,[23][24][25] Uehata et al found per os treatment with Y-27632 to result in a significant decrease in blood pressure in hypertensive, but not normotensive, rats. 23 Additionally, pre-contracted (with phenylephrine or serotonin) endothelium denuded mesenteric arteries from mineralocorticoid or angiotensin-II treated rats displayed an increase in vasodilator sensitivity to Y-27632.…”

“…23 Additionally, pre-contracted (with phenylephrine or serotonin) endothelium denuded mesenteric arteries from mineralocorticoid or angiotensin-II treated rats displayed an increase in vasodilator sensitivity to Y-27632. 1,24 An increase in vascular Rho-kinase activity in hypertension suggests a possible mechanism by which hypertension may correlate with a decreased erectile response. In this study, we establish the presence of a decreased erectile response in hypertensive rats, and hypothesize that this dysfunction is mediated by increased Rho-kinase activity in the cavernosal arterioles and sinus governing the regulation of the erectile state.…”

Hypertension and RhoA/Rho-Kinase Signaling in the Vasculature

“…We have also examined the relaxation response to Y-27632 in superior mesenteric arteries isolated from rats after 13 days of angiotensin II-induced hypertension. 20 After contraction induced with phenylephrine, mesenteric arteries (no endothelium) relaxed in a concentration-dependent fashion in response to Y-27632. The relaxation of arteries from hypertensive rats demonstrated a leftward shift in the concentration response curve to Y-27632 compared with normotensive values, suggesting that vessels from the angiotensin IIinduced hypertensive animals have an increased sensitivity to Rho-kinase inhibition.…”