Excellence Award in Hypertension Research Vascular Remodeling in Hypertension Mechanisms and Treatment

Over the past few years noninvasive and invasive techniques have allowed a better appreciation of vascular changes in hypertensive humans and experimental animals.1 Large arteries undergo outward hypertrophic remodeling and increased stiffness with aging,2–4 and in hypertension there may be an acceleration of this process leading to enhanced pulse pressure. A reduced aortic diameter in middle-aged hypertensive subjects may also play a role in increases in pulse pressure through increased specific impedance,5 contradicting the classic hypertensive aortic phenotype characterized by vascular wall degeneration and calcification and increased aortic diameter. In advanced hypertension, however, the elastic laminae undergo duplication and fragmentation, with increased deposition of collagen and fetal (EIIIA) fibronectin, contributing to increased stiffness. Classically the remodeling of small arteries in hypertension has been associated with increased media thickness, but recent studies have demonstrated that 2 types of remodeling are found, inward eutrophic or inward hypertrophic remodeling, depending on whether the media cross-sectional area is enlarged (true hypertrophy). 6–9 Although eutrophic remodeling is usually found in essential (primary) hypertension in humans and spontaneously hypertensive rats (SHRs); in secondary hypertension such as in renovascular hypertension, primary aldosteronism, or in pheochromocytoma10; in hypertension associated with diabetes mellitus11,12; and in acromegaly,13 hypertrophic remodeling has been described. In mineralocorticoid hypertension in rodents14,15 and in salt-sensitive Dahl rats,16 in both of which the endothelin (ET) system is activated, remodeling of small arteries is also hypertrophic (see below). Thus, when the renin-angiotensin system is even mildly activated (primary hypertension and SHRs), remodeling is usually eutrophic. In salt-dependent hypertension, diabetes mellitus, and malignant hypertension, all conditions in which the ET system is activated, remodeling is hypertrophic.17 Hyperplasia of vascular smooth muscle cells (VSMCs) is found in small arteries of hypertensive rats, whereas in the aorta, VSMC hypertrophy has been reported.18,19 In essential hypertension, cell volume and number in small arteries are similar to those of normotensive subjects.20 The mechanisms leading to inward eutrophic remodeling are poorly understood but could result from inward growth combined with peripheral apoptosis or from vasoconstriction embedded in an expanded extracellular matrix.21 Indeed, there is deposition of collagen and fibronectin with increased collagen:elastin ratio in small vessels from hypertensive humans and rodents,22,23 which may be induced by ET,24 angiotensin (Ang) II, and aldosterone25 acting in an endocrine or paracrine fashion. The potential remodeling role of tissue transglutaminases that generate interactions of extracellular matrix fibrillar components with attachment sites on VSMCs has been reported recently.26 In the remodeled artery, with rearranged cellular and fibrillar components attributed to changes in interaction of these structures through integrins 27 , collagen fibers are recruited at higher distending pressures in vessels that accordingly initially exhibit decreased stiffness, although later stiffness is enhanced. Low-grade inflammation of both the arterial wall and perivascular fat participates as well in arterial remodeling28 (see below), characterized by inflammatory cell infiltration, upregulation of inflammatory mediators, such as vascular cellular adhesion molecule 1, intercellular adhesion molecule 1, nuclear factor (NF)B, monocyte chemoattractant factor 1, and plasminogen activator inhibitor 1, and enhanced oxidative stress. Small artery remodeling may be the first manifestation of target organ damage in hypertension, because in our series of patients, 100% of stage I hypertensive subjects present small artery remodeling, whereas only 60% have endothelial dysfunction (see below) and 45% left ventricular hypertrophy.29 Follow-up of patients in who investigation of small artery structure was performed has demonstrated the prognostic significance of small artery remodeling,30 because hypertensive patients with the highest media:lumen ratio had increased incidence of cardiovascular events. Dysfunction of the endothelium is often associated with elevation of blood pressure (BP) and may be a secondary phenomenon that does not initiate BP elevation; rather, it may be associated with cardiovascular risk factors that cluster with hypertension, such as smoking, obesity, dyslipidemia, metabolic syndrome, and diabetes mellitus. It may contribute to