Vascular Aging: Implications for Cardiovascular Disease and Therapy

Abstract

The incidence and prevalence of cardiovascular disease is highest among the elderly, in part, due to deleterious effects of advancing age on the heart and blood vessels. Aging, a known cardiovascular risk factor, is progressively associated with structural and functional changes to the vasculature including hemodynamic disturbance due to increased oxidative stress, premature cellular senescence and impairments in synthesis and/or secretion of endothelium-derived vasoactive molecules. These molecular and physiological changes lead to vessel wall stiffening and thickening, as well as other vascular complications that culminate to loss of vascular tone regulation and endothelial function. Intriguingly, the vessel wall, a biochemically active structure composed of collagen, connective tissue, smooth muscle and endothelial cells, is adversely affected by processes involved in premature or normal aging. Notably, the inner most layer of the vessel wall, the endothelium, becomes senescent and dysfunctional with advancing age. As a result, its ability to release vasoactive molecules such as acetylcholine (ACh), prostacyclin (PGI2), endothelium-derived hyperpolarizing factor (EDHF), and nitric oxide (NO) is reduced and the cellular response to these molecules is also impaired. By contrast, the vascular endothelium increases its generation and release of reactive oxygen (ROS) and nitrogen (RNS) species, vasoconstrictors such as endothelin (ET) and angiotensin (AT), and endogenous inhibitors of NO synthases (NOSs) to block NO. This skews the balance of the endothelium in favor of the release of highly tissue reactive and harmful molecules that promote DNA damage, telomere erosion, senescence, as well as stiffened and hardened vessel wall that is prone to the development of hypertension, diabetes, atherosclerosis and other cardiovascular risk factors. This Review discusses the impact of advancing age on cardiovascular health, and highlights the cellular and molecular mechanisms that underlie age-associated vascular changes. In addition, the role of pharmacological interventions in preventing or delaying age-related cardiovascular disease is discussed.

Keywords: Cardiovascular health; Endothelial senescence; Endothelium; Vascular aging; Vascular function; Vascular pharmacology; Vascular rejuvenation.

Figure 1

Senescence and rejuvenation of vascular endothelium. A) Aging or vascular injury contributes to endothelial dysfunction and senescence including increased endothelial permeability, over-proliferation of smooth muscle cells (SMCs), adhesion of inflammatory monocytes, accumulation of reactive oxygen species (ROS), peroxynitrite (OONO⁻), and inflammatory cytokines. In addition, the number of endothelial precursor cell reserve such as endothelial progenitor cells (EPCs) and endothelial colony-forming cells (ECFCs) is markedly reduced. In B) a rejuvenated vascular endothelium, as a result of pharmacological intervention, characterized by continuous monolayer of endothelial cells and production of beneficial vasoactive molecules such as nitric oxide (NO), as well as enriched EPCs and ECFCs is shown.