Angiotensin II and the Endothelium

Abstract

Abstract-The initial view of the renin-angiotensin system focused on the role of angiotensin II as a hormone involved in blood pressure control, based on its role in renal salt and water regulation, as well as central nervous system (thirst) and vascular smooth muscle tone. Subsequent data showed a role for angiotensin II in long-term effects on cardiovascular structure, including cardiac hypertrophy and vascular remodeling. I n this review, we discuss the evolving role of angiotensin II (Ang II) as a regulator of endothelial cell (EC) function. In particular, recent clinical trials of angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor blockers (ARBs) suggest that several of the beneficial effects of these drugs are mediated by inhibiting Ang II effects at the endothelium. Initially, Ang II was identified as a hormone that controlled blood pressure based on regulation of renal salt and water metabolism, central nervous system mechanisms (thirst and sympathetic outflow), and vascular smooth muscle cell (VSMC) tone. 1 Later, Ang II was found to exert long-term effects on tissue structure, including cardiac hypertrophy, vascular remodeling, and renal fibrosis. Importantly, recent human studies with ACE inhibitors and ARBs have yielded exciting clinical benefits such as decreased incidence of stroke, diabetes mellitus, and end-stage renal disease. 2,3 This article discusses the endothelium-specific effects of these drugs and Ang II, based on the concept of diverse signals and effects mediated by multiple angiotensin receptors (AT 1 R, AT 2 R, and AT 4 R), multiple angiotensin I-and Ang II-derived peptides [Ang III, Ang IV, and Ang (1-7)], and vascular bed-specific events (Figure 1). The enzymes that control generation of these peptides, including ACE, ACE2, endopeptidases, and aminopeptidases, interact with each other. In addition, drugs such as ACE inhibitors and ARBs that inhibit formation of Ang II and binding to its receptor also modify the expression of receptors for Ang II and of other vasoactive hormones, including bradykinin and adrenomedullin. This complex interplay of pathways helps to explain the findings that Ang II can have both beneficial and detrimental effects on vascular function. Effects of Angiotensin Type-1 ReceptorThe AT 1 R has been shown to mediate most of the physiological actions of Ang II. However, as discussed, important regulatory roles for the AT 2 R and AT 4 R, have been defined, especially in EC. Recent data show several pathways by which the AT 1 R and AT 2 R modulate EC function. 4 ApoptosisAng II has been shown both to increase and decrease EC apoptosis, suggesting that other factors influence the actions of Ang II (eg, presence of oxidized low-density lipoprotein [oxLDL]). In fact, both the AT 1 R and the AT 2 R have been suggested to mediate EC apoptosis. 5,6 As discussed further, we speculate that the relative AT 1 R and AT 2 R expression levels are important determinants of the effects of Ang II in EC (Figure 2). Ang II-mediated EC apoptosis is in part mediated b...

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