Hypertension and RhoA/Rho-Kinase Signaling in the Vasculature

Abstract

Abstract-Under normal conditions, contractile activity in vascular smooth muscle is initiated by either receptor activation (norepinephrine, angiotensin II, etc.) or by a stretch-activated mechanism. After this activation, several signaling pathways can initiate a Ca 2ϩ -calmodulin interaction to stimulate phosphorylation of the light chain of myosin. Ca 2ϩ sensitization of the contractile proteins is signaled by the RhoA/Rho-kinase pathway to inhibit the dephosphorylation of the light chain by myosin phosphatase thereby maintaining force generation. In opposition to force generation, NO is released from endothelial cells and causes vasodilation through inhibition of the RhoA/Rho-kinase signaling pathway. This brief review will highlight recent studies demonstrating a role for the RhoA/Rho-kinase signaling pathway in the increased vasoconstriction characteristic of hypertension. Key Words: vasculature Ⅲ signal transduction Ⅲ muscle, smooth Ⅲ nitric oxide Ⅲ vasoconstriction I ncreased peripheral vascular resistance causes elevated arterial pressure in hypertension. Arterial wall thickening, increased vasoconstriction, and reduced vasodilation contribute to this increased peripheral resistance. Multiple regulatory processes (neural, humoral, etc.) and complex cell signaling pathways modulate vascular smooth muscle cell (VSMC) contraction, relaxation, and growth. Under normal conditions, these regulatory processes maintain vessel wall integrity and do not contribute to pathological increases in blood pressure. Remodeling of the vasculature in hypertension involves rearrangement of cellular and extracellular components and has been reviewed extensively. [1][2][3][4][5][6] The present review highlights recent developments in the understanding of cellular and molecular mechanisms underlying increased vasoconstriction in hypertension with an emphasis on the RhoA/Rhokinase signaling pathway in vascular smooth muscle. Contractile MechanismVascular smooth muscle contraction is principally regulated by receptor and mechanical (stretch) activation of the contractile proteins. 7 Depolarization of the plasma membrane can also trigger contraction. For contraction to occur, myosin light chain (MLC) kinase must phosphorylate the light chain of myosin, enabling the cycling of myosin cross-bridges with actin. 7-9 Thus, contractile activity is determined primarily by the phosphorylation state of the light chain of myosin. 8,9 In VSMCs of some blood vessels, phosphorylation of the light chain of myosin is maintained at a low level in the absence of external stimuli (ie, no receptor or mechanical activation). This activity results in what is known as myogenic tone.Recent work suggests that 20-HETE may play a signaling role in the myogenic response of pig coronary arteries. Randriamboavonjy et al 10 observed that 20-HETE elicited contraction and phosphorylation of the light chain of myosin. Both of these activities were inhibited by Y-27632, a Rhokinase inhibitor (see below for description of signaling pathway). Ca 2؉ -Dependent Con...

Creatine Kinase Activity Is Associated With Blood Pressure

“…3 Calciumdependent, RhoA/Rho kinase and nitric oxide (NO)-guanosine 3Ј,5Ј-cyclic monophosphate pathways, the main intracellular effectors of blood pressure-regulating systems in vascular smooth muscle, converge on metabolic processes fueled by CK (Figure 2). [3][4][5][6]38,[42][43][44][45][46] Vascular smooth muscle contraction is thought to consist of a fast, force-generating component at relatively high energy costs and a slow, tonic maintenance of tension, 6 thought to depend on the ability to have attached but dephosphorylated cross-bridges (latch bridges), 47,48 for which ADP is required. 49 The latch bridge is formed when a phosphorylated myosin head is dephosphorylated while attached to actin.…”

“…NO, RhoA/Rho kinase, and calcium-dependent pathways are intracellular effectors of blood pressure-regulating systems that converge on metabolic processes fueled by CK. [3][4][5][6]38,[42][43][44][45][46] CK is colocalized with Ca 2ϩ -ATPase and myosin ATPase, and evidence suggests the enzyme is also colocalized with myosin light chain kinase (MLCK), to rapidly supply these enzymes with ATP using creatine phosphate. [3][4][5][6] High CK activity, particularly at myosin ATPase in resistance arteries, 38 could directly enhance pressor responses, with a great impact on blood pressure.…”

Proteome Analysis of Cultivated Vascular Smooth Muscle Cells from a CADASIL Patient

“…Therefore, the upregulation of RhoGDI indicates upregulation of the Rho family GTPases and enhanced signaling of the Rho family GTPase-regulated pathways, including VSMC contraction. Rho family GTPases can be activated by angiotensin II, the hypertension-inducing effector molecule in the renin-angiotensin system involved in the regulation of blood pressure (37,38). Rho family GTPases activate Rho kinases (39) and a signaling cascade which leads to increased microtubule phosphorylation and facilitation of microtubule disassembly, actin filament assembly, and finally, promotion of smooth muscle contraction (40)(41)(42).…”

Rho-Kinase Inhibitor Improves Increased Vascular Resistance and Impaired Vasodilation of the Forearm in Patients With Heart Failure

“…44 For example, it is suggested that NO induces vasodilation through inhibition of the Rho/Rho-kinase signaling pathway and that the Rho/Rho-kinase activity negatively regulates endothelial NO synthase phosphorylation. 45 It is well established that NO activity is decreased in HF. 6 -10 In addition, we previously demonstrated that L-arginine supplementation improves both acetylcholine-induced and reactive hyperemia-induced forearm vasodilation in patients with HF, which suggests that the impaired vasodilation is caused by reduced NO activity in HF.…”