Vascular Fibrosis in Aging and Hypertension: Molecular Mechanisms and Clinical Implications

Abstract

Aging is the primary risk factor underlying hypertension and incident cardiovascular disease. With aging, the vasculature undergoes structural and functional changes characterized by endothelial dysfunction, wall thickening, reduced distensibility, and arterial stiffening. Vascular stiffness results from fibrosis and extracellular matrix (ECM) remodelling, processes that are associated with aging and are amplified by hypertension. Some recently characterized molecular mechanisms underlying these processes include increased expression and activation of matrix metalloproteinases, activation of transforming growth factor-β1/SMAD signalling, upregulation of galectin-3, and activation of proinflammatory and profibrotic signalling pathways. These events can be induced by vasoactive agents, such as angiotensin II, endothelin-1, and aldosterone, which are increased in the vasculature during aging and hypertension. Complex interplay between the “aging process” and prohypertensive factors results in accelerated vascular remodelling and fibrosis and increased arterial stiffness, which is typically observed in hypertension. Because the vascular phenotype in a young hypertensive individual resembles that of an elderly otherwise healthy individual, the notion of “early” or “premature” vascular aging is now often used to describe hypertension-associated vascular disease. We review the vascular phenotype in aging and hypertension, focusing on arterial stiffness and vascular remodelling. We also highlight the clinical implications of these processes and discuss some novel molecular mechanisms of fibrosis and ECM reorganization.

Association Between Elevated Pulse Pressure and High Resting Coronary Blood Flow Velocity in Patients With Angiographically Normal Epicardial Coronary Arteries

“…Arterial stiffness, which is a natural consequence of aging, is accelerated in arterial hypertension and is primarily caused by reduced elasticity and excessive fibrosis, which involves both large and small arteries. In conduit arteries, vascular stiffening is associated with hemodynamic damage of peripheral tissues, while, in the resistance circulation, fibrosis and stiffening can alter endothelial function, leading to elevated vasomotor tone and vascular rarefaction and thus impairing tissues perfusion 5. This explains why our patients with PP >60 mm Hg, identified by HPPT, presented higher coronary flow velocity at rest and reduced CFR.…”

“…The association between resting coronary flow velocity and HPPT, then, is not merely due to the elevated values of systolic BP, which is crucial for the characterization of PP but not the only determinant. The association with HPPT is largely justified by the influence of increased arterial stiffness on coronary flow at rest: more rigid the arterial wall, higher the workload required to keep an adequate coronary flow 5. Coronary flow velocity at rest was also associated with LV mass, which can increase the extravascular resistance of coronary microvessels by the compressive force of myocardial fibrosis 39, 45, 47, 49.…”

“…These patients could benefit from more aggressive management of cardiovascular risk factors, in particular, BP control and administration of drugs for cardiac prevention (eg, statins). Since the fibrogenic process is progressive and potentially reversible,5 the identification of patients at risk, also at a preclinical stage, and timely treatment might avoid the progression of cardiovascular impairment.…”

“…Increased PP exhibits a wide range of values, depending on increased systolic BP, decreased diastolic BP, or both. PP is a raw index of arterial stiffness, since loss of arterial elasticity demands greater force to accommodate blood flow, leading to increased systolic BP, increased cardiac workload, and consequent cardiac4 and vascular remodeling 5. Arterial wall stiffening affects peripheral small arteries and microcirculation 6, 7, 8, 9.…”

Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats

“…These data provide direct evidence that SHR TA VSMCs are able to impact collagen construction in aortic tissue. These results from the in vitro tissue resemble ECM topography detected in stiffening aorta and other arteries in vivo (Dodson et al., 2013; Harvey, Montezano, Lopes, Rios & Touyz, 2016) and thus emphasize the effect of VSMCs upon ECM remodeling and contribute to the aortic stiffening in SHR.…”