In addition to its potent effects on vasoconstriction and BP control, Ang II also exerts a variety of effects on vascular biology, which are independent of vascular tone and pressure. AT1 receptors are expressed in most vascular cell types, including endothelial and VSMCs, cardiomyocytes, and cardiac fibroblasts (23). Activation of these receptors affects a diverse array of vascular cell functions including growth, migration, oxidant production, and gene expression (100). Overproduction of Ang II and/or increased Ang II sensitivity within the vasculature tissues may stimulate these cellular processes and thereby contribute to vascular remodeling, hypertrophy, fibrosis, thrombosis, and atherosclerosis. Consistent with this hypothesis, ACE inhibition and AT1 blockade have been shown to reduce perivascular fibrosis, PAI-1, and matrix metalloprotease expression in normotensive insulin-resistant diabetic rodents (112,113). Additionally, AT1 antagonism has been shown to reduce neointimal thickening of balloon catheter-injured vessels in diabetic Wistar fatty rats (114). Local activation of the RAS may have particular importance at sites of vascular injury or atherosclerosis, which have locally elevated ACE- and chymase-mediated Ang II production and upregulation of AT1 receptors (26,27,48,115). Activation of AT1 receptors expressed on monocytes and macrophages may contribute to atherogenesis by increasing arterial thrombosis and inflammatory responses (116-118). Given that components of Ang II generation and Ang II receptors (AT1 and AT2) are coexpressed in RAS target tissues, and the half-life of circulating Ang II is only 14 to 16 seconds (46,47), it is likely that autocrine/paracrine actions of the RAS system play a major role in the BP-independent effects in vascular tissues.
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