Hypertension, diabetes, and atherosclerosis are three dis-eases responsible for the majority of cardiovascular morbidity in humans. Not only are they independent risk factors, but they clearly potentiate and complement each other in the pathogenesis of cardiovascular disease. The first manifestation of end-organ damage in these diseases is the vascular remodeling of small (resistance) and large (conductance), and this precedes the development of cardiac hypertrophy, renal insufficiency or stroke. 1 This vascular remodeling is characterized by hyperplasia, hypertrophy, and apoptosis of smooth muscle cells (SMCs) and vascular fibrosis, caused by increased extracellular matrix deposition of total collagen, and changes in ratio of type I/III collagen, fibronectin, and proteoglycans. 1 Angiotensin II (Ang II) has recently emerged as a key mediator of vascular fibrosis (sclerosis) both in humans and animal models of hypertension because of its pleiotropic effects of SMCs, fibroblasts, and inflammatory cells. Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor antagonists (ARB) diminish cardiac hypertrophy and vascular fibrosis in animal models of hypertension. 1, 2 In human clinical trials of hypertension, ARBs reverse vascular remodeling in resistance arteries and new incidence of strokes more potently than any other antihypertensive agents (beta-blockers or calcium channel blockers), despite similar reduction in blood pressure. 3, 4 This provides strong evidence that targeting the mechanisms involved in arterial remodeling process may provide the key in preventing the long-term consequences of hypertension or atherosclerosis in humans.

However, deciphering the intimate mechanisms of in vivo vascular remodeling has become very complex because of enormous reciprocal interactions between Ang II and other growth factors. Ang II exerts its effects not only by activating its specific receptors, but also by transactivating other growth factor receptors such as epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), platelet-derived growth factor receptor (PDGF-R), 1 or type III transforming growth factor receptor (endoglin). 5 Whereas these pathways mediate the acute effects of Ang II, long-term outcomes of Ang