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.

Figure 1

The vascular phenotype in aging and hypertension. With aging and during the development of hypertension, the endothelium, vascular wall, and adventitia undergo functional and structural changes. Endothelial function is impaired and the vascular media is thickened. The adventitial extracellular matrix undergoes remodelling, with increased collagen deposition, reduced elastin content, and increased proinflammatory cells. These processes contribute to vascular fibrosis and stiffening. ECM, extracellular matrix; MMP, matrix metalloproteinases; TIMPs, tissue inhibitory metalloproteinases; VSMC, vascular smooth muscle cell.

Figure 2

Vascular signalling mediating extracellular matrix (ECM) remodelling, fibrosis, and arterial stiffening in aging and hypertension. Prohypertensive factors and physiological aging promote ECM remodelling through activation of transforming growth factor-β (TGF-β) and subsequently, mitogen-activated protein kinase (MAPK) and SMAD pathways, reactive oxygen species (ROS) production, leading to matrix metalloproteinase (MMP) and connective tissue growth factor (CTGF) activation and upregulation of galectin-3. Subsequently, collagen, fibronectin, and proteoglycan deposition is increased, leading to fibrosis and increased arterial stiffness. PAI, plasminogen activator inhibitor.

Figure 3

Influence of prohypertensive factors and aging in the development of vascular fibrosis and arterial stiffening. The renin-angiotensin-aldosterone system, acting through angiotensin receptor type 1 (AT1R) and mineralocorticoid receptor (MR), and endothelin-1 (ET-1) acting through endothelin receptor (ETR) activate matrix metalloproteinase (MMPs), connective tissue growth factor (CTGF), and transforming growth factor-β (TGF-β) signalling, resulting in inflammation, oxidative stress, and fibrosis, leading to increased arterial stiffness. This process is also induced by ET-1 signalling through ETR, aldosterone signalling through MR, and aging. ACE, angiotensin converting enzyme.