Arteriosclerosis is the process of age-related large artery stiffening usually found in individuals with wide PP or systolic hypertension. This adventi-tial and medial process must be differentiated from atherosclerosis, the occlusive low-grade endovascular inflammatory process that results from endothe-lial dysfunction and lipid oxidation. Arteriosclerosis often coexists with atherosclerosis but is worth differentiating from the former because prevention and treatment of the two conditions probably differ significantly. Histo-pathologically, arteriosclerosis is a diffuse non-inflammatory fibrotic process affecting primarily the adventitia and media, with breakdown of elastin, increased collagen and matrix deposition, and VSM hypertrophy . Changes in other arterial wall components such as the vasa vasora may contribute to arteriosclerosis because occlusion of these adventitial vessels tends to increase the collagen:elastin ratio and arterial stiffness .
The difference between 'usual' and 'optimal' aging and the related question of the etiology of arteriosclerosis remain unclear. Nevertheless, over a lifetime, excessive burdens of pressure (causing cellular deformation and hypertrophy) and pulsatile flow (cyclic shear stress) are likely contributors to reduced elasticity and increased wall stiffness. Age-related dilation usually occurs in large arteriosclerotic arteries [27, 28], increasing PWV, while it minimally affects Zc [9, 10, 19]. Metabolic phenomena, including oxidative burden and different forms of cross-linking of proteins in the arterial wall, may be important as well. Overstimulation of physiologic systems can also influence arterial structure and function. In rats, chemical sympathectomy acutely increases aortic diameter and compliance but chronically reduces elastin content, vessel diameter and distensibility . Exercise conditioning in rats reduces sympathetic nervous activity and lowers BP but does not affect the proportion of elastin or arterial wall constituents . There are several lines of evidence that suggest a role for the renin-angiotensin-aldosterone system as an important modulator of arterial properties. Angiotensin II increases aortic wall thickness and stiffness in rats [31, 32]. Aldosterone administration revers-ibly increases rat aortic stiffness and fibronectin content in dose-dependent fashion independent of wall stress, with no changes in collagen or elastin . Arterial stiffness in humans has been related to genetic variation in components of the renin-angiotensin-aldosterone system. Variability in PWV has been related to polymorphisms in the angiotensin II receptor (AGTR1) [34, 35], while variation in PP has been related to genetic variation in the angioten-sin-converting enzyme gene .
Chronic structural changes are at least partially reversible, suggesting a tonic dependence on mechanical and neurohumoral inputs. Compared to an-giotensin-converting enzyme inhibition alone, there are greater improvements in human Zc caused by neutral endopeptidase inhibition (which increases atriopeptins and further augments bradykinin) . Matrix metalloprotein-ases are sensitive to nitric oxide, so neutral endopeptidase inhibition inhibitors may directly affect remodeling of vessels. The idea that aortic stiffness is largely independent of distal vascular resistance has practical applications for the future in the form of drugs that may reduce aortic stiffness by affecting large arterial wall components, especially those that block or disrupt collagen crosslinks without affecting arteriolar function .
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