Role of the renin angiotensin aldosterone system in vascular endothelial function

The endothelium has numerous vital functions. First, it acts as a permeability barrier preventing exocytosis of macrophage and small, dense low-density lipoprotein (LDL) entering the subendo-thelial layer from initiating the genesis of the fatty streak, the first step in atherosclerosis. Second, it is important in maintaining vascular tone by releasing angiotensin II and endothelin, powerful vasoconstrictors, and balancing that release by the release of nitric oxide, a potent vasodilator. The endothelium also plays an active role in hemosta-sis, mediating coagulation by inhibiting platelet aggregation and by releasing von Willebrand's factor, tissue plasminogen activator (PAI), and RAAS. It also releases cell adhesion molecules and inflammatory cytokines such as interleukin-6, tumor necrosis factor (TNF) alpha, and others that are involved in the process of atherosclerosis. Finally, it acts as a transducer of biomechanical forces and prevents shear stress from denudating the endothelial layer to allow plaque accumulation (Fig. 3) [51,52]. Angiotensin II contributes to endothelial dysfunction by increasing oxidative stress, attenuating chemoattractants, and increasing adhesion molecule expression leading to inflammation [53]. In addition, angiotensin II can

Fig. 1. Renin angiotension aldersterone system pathway. AT I, angiotensin receptor type I; AT II, angiotensin receptor type II; ECM, extracellular matrix; VSMC, vascular smooth muscle cell.
Fig. 2. Angiotensin II and the sequential progression of cardiovascular disease. CAD, coronary artery disease; DM, diabetes mellitus; HTN, hypertension; LVH, left ventricular hypertrophy.

exert proliferative and prothrombotic activity, producing superoxide radicals that scavenge nitric oxide and reducing vasodilation [54]. There is evidence that an increased expression of ACE is present in endothelial growth arrest [54]. ACE is induced by glucocorticoids in vascular smooth muscle [55]. Activation of ACE induces PAI-1

levels that contribute to atherothrombosis [56]. Bradykinin, which is unopposed with blockade of ACE, has significant beneficial effects on endo-thelium, primarily from its powerful vasodilating properties [57,58]. Thus, there is evidence that accumulation of angiotensin II impairs endothe-lial function and enhances atherogenic process.

Macrophage

Endothelial Cell

Smooth Muscle Cell

Macrophage

Endothelial Cell

Smooth Muscle Cell

PDGF

Proliferation

Hypertrophy

Apoptosis

modulation

PDGF

Proliferation

Hypertrophy

Apoptosis

modulation

Fig. 3. Role of angiotension-converting enzyme in vascular function. AII, angiotensin II; ECM, extracellular matrix; FGF, fibroblast growth factor; MCP, monocyte chemotactic protein; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; VCAM, vascular cell adhesion molecule.

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