ANGIOTENSIN II, a crucial regulator of the cardiovascular system, is not only required for physiological functions, such as maintenance of blood pressure and plasma sodium concentration but also is involved in pathophysiological conditions such as hypertension and atherosclerosis (26). Angiotensin II exerts its effect by mainly binding to the angiotensin II type-1 (AT 1 ) receptor. As its seven transmembrane structure suggests, the AT 1 receptor couples to several heterotrimeric G proteins including G q . In addition, the activation of the AT 1 receptor leads to increased reactive oxygen species; activation of various protein tyrosine and serine/threonine kinases; and of small G proteins such as Ras, Rac, and RhoA, which may require heterotrimeric G protein-dependent and -independent mechanisms (6,7,11,19).Among the downstream components involved in angiotensin II signal transduction, RhoA and its effecter Rho-kinase/ ROCK have attracted particular interest as novel therapeutic targets (18). RhoA, a member of the Rho family of small GTP binding proteins, is abundantly expressed in vascular smooth muscle (12) and is well known to participate in arterial smooth muscle contraction via Ca 2ϩ sensitization (4). Moreover, the RhoA/ROCK pathway has been implicated in a wide variety of disease conditions in the cardiovascular system, including hypertension, atherosclerosis, arterial restenosis, myocardial ischemia, and cardiac hypertrophy/fibrosis in animal models as well as in humans (9,15,23).The Rho protein functions as a molecular switch that cycles between the active GTP-bound form and inactive GDP-bound form. GDP/GTP exchange is facilitated by guanine nucleotide exchange factors (GEFs) that catalyze the exchange of GDP to GTP and by GTPase activating proteins (GAPs) that accelerate the hydrolysis of the GTP to GDP (21). In this regard, many G protein-coupled receptors (GPCRs) are believed to increase RhoA activity via the G 12/13 family of G proteins through activation of their effectors, the RGS domain-containing RhoGEFs (p115 RhoGEF, PDZ-RhoGEF, and LARG are the known members) (20, 29). The presence of this "basic" mechanism of RhoA/ROCK regulation by a GPCR has been shown in the AT 1 receptor activation of vascular smooth muscle cells (VSMCs) and cardiac myocytes in culture (14, 24) and in vivo for arterial contraction stimulated by angiotensin II (28). However, studies published recently (1, 27) also suggest that the regulation of RhoA/ROCK by the AT 1 receptor is not limited to the G 12/13 /RGS domain-containing RhoGEF pathway.