Received for publication August 10, 2005.
Revised December 11, 2005.
Accepted for publication December 13, 2005.

Angiotensin II Up-regulates Leukemia-associated Rho Guanine Nucleotide Exchange Factor (LARG), a RGS Domain Containing RhoGEF, in Vascular Smooth Muscle Cells

Abstract

In vascular smooth muscle, stimulation of heterotrimeric G-protein-coupled receptors (GPCR) by various contractile agonists activates intracellular signaling molecules to result in an increase in cytosolic Ca²⁺ and the subsequent phosphorylation of myosin light chain (MLC) by Ca²⁺/calmodulin-dependent MLC kinase (MLCK). Additionally, a portion of agonist-induced contraction is partially mediated by the Ca²⁺-independent activation of the small G-protein, RhoA, and a downstream target, Rho-kinase. The activation of RhoA is controlled by several regulatory proteins, including guanine nucleotide exchange factors (GEFs). GEFs activate RhoA by promoting the release of GDP and then facilitating the binding of GTP. There are three Rho-specific GEFs (RhoGEFs) in vascular smooth muscle that contain a binding domain [regulator of G protein signaling (RGS) domain] capable of linking GPCRs to RhoA activation: PDZ-RhoGEF, LARG (leukemia-associated RhoGEF), and p115RhoGEF. We hypothesized that RGS domain containing RhoGEFs, especially LARG, participate in linking GPCR to RhoA activation in vascular smooth muscle. We observed that angiotensin II up-regulates LARG via the AT1 receptor, and this up-regulation is signaled via the phosphatidylinositol 3-kinase (PI3-kinase) pathway. Further, angiotensin II treatment caused a small, but significant, increase in the component of contractile responses sensitive to Rho-kinase antagonism. These observations support the hypothesis that RhoGEFs, particularly LARG, participate in linking GPCR to RhoA activation in vascular smooth muscle.

Key words: Angiotensin, RGS proteins, Cdc42, rho, rac, other small G proteins, NFkappaB, Promoter analysis

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