As part of the inflammatory response, tissues undergo repair. This process involves cell growth and fibrosis, both of which are modulated by Ang II (Fig. 1). Ang II influences cell growth by stimulating hyperplasia, hypertrophy, and apoptosis (77). In cultured VSMC through the ATjR, Ang II induces hyperplasia (increase in cell number associated with DNA synthesis) or hypertrophy (increased protein synthesis and/or increased intra-cellular cell water volume). These effects are partially mediated through transactivation of EGFR, PDGFR, and IGFR and involve activation of growth-signaling pathways including c-Src and MAP kinases (78-80). Vascular cell hyperplasia and hypertrophy contribute to remodeling associated with vascular injury and inflammation (81,82). Ang II also has antigrowth and pro-apoptotic actions, mediated primarily through AT2R (83-85). These effects are particularly important in pathological conditions associated with vascular inflammation in which AT2R may be upregulated, such as in aortic banding-induced hypertension (86), renal injury (87), myocardial infarction (88), and in human atherosclerotic coronary arteries (89).
Vascular fibrosis, an important component in the inflammatory-reparative process, involves accumulation of extracellular matrix proteins, particularly collagen and fibronectin, in the vascular media and contributes to structural remodeling and scar formation. Ang II is critically involved in fibrosis. In cultured VSMCs, fibroblasts and cardiac cells, Ang II stimulates profibrotic signaling pathways and stimulates production of vascular collagen and fibronectin (77,90-92). Systemic infusion of Ang II leads to cardiac, vascular, and renal fibrosis, which is prevented by AT1R blockade (93). Studies in ATjR-deficient mice further confirm the importance of Ang II in cardiovascular fibrosis (94,95). In addition to stimulating collagen production, Ang II influences extracellular matrix composition by inducing collagen degradation by attenuating interstitial matrix metalloproteinase (MMP) activity and by enhancing tissue inhibitor of metalloproteinase (TIMP)-1 production (96). In young SHR, activity of MMP1 and MMP3 is reduced (52), whereas in adult SHR, MMP2 activity is decreased (96). These effects promote accumulation of fibronectin, proteoglycans, and collagen, which contribute to remodeling in hypertension. AT1R blockade normalized TIMP-1 expression and collagenase activity, supporting the role for Ang II in these processes (96).
Ang II-elicited growth and profibrotic effects are modulated by the endogenous production of various mitogenic factors, such as TGF-P, PDGF, and ET-1 (97-101). Of these, TGF-P, a multifunctional cytokine, appears to be particularly important. TGF-P increases extracellular matrix biosynthesis, downregulates matrix degradative enzymes and influences integrin receptors (102). TGF-P is synthesized by macrophages, lymphocytes, fibroblasts, VSMCs, and renal cells (102). Vascular and renal injury induced by hypertension, diabetes and/or the RAS appear to be mediated by overexpression and conversion of TGF-Pj from its latent form to its active form (103). Activation of latent TGF-Pj is preceded by overexpression of thrombospondin-1 (104), an extracellular matrix protein responsible for its activation. Invading monocytes expressing TGF-Pj also contribute to vascular TGF-Pj overexpression. TGF-Pj elicits its effects by interacting with two cell surface membrane signaling receptors, a type II TGF-P receptor and a type I receptor (ALK-5). Signals from the activated TGF-P receptor complex are transduced to the nucleus by Smad proteins, a family of transcription factors recently implicated as intracellular mediators of inflammation (105). Key downstream profibrogenic mediators of TGF-P include p38MAP kinase and connective tissue growth factor (CTGF). CTGF mediates Ang II-stimulated cardiac fibroblast activation in heart failure and is a potent inducer of vascular and renal fibro-sis (106-108). Furthermore, Ang II increases CTGF mRNA expression and production (9,106,109,110). TGF-P is negatively regulated by unique proto-oncoproteins, Ski, and SnoN (111). It is clear that TGF-P is a fundamental pathogenic cytokine that is consistently overexpressed in many cardiovascular and renal disorders associated with activation of the RAS. In support of this, inhibition of the RAS with ACE inhibitors or ATjR blockers is closely correlated with the suppression of TGF-P production and amelioration of fibrosis (103,112).
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