Novel Contributors and Mechanisms of Cellular Senescence in Hypertension-Associated Premature Vascular Aging

Abstract

Hypertension has been described as a condition of premature vascular aging, relative to actual chronological age. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated in hypertension. Nonetheless, the precise mechanisms that underlie the aged phenotype of arteries from hypertensive patients and animals remain elusive. Cellular senescence is an age-related physiologic process in which cells undergo irreversible growth arrest. Although controlled senescence negatively regulates cell proliferation and promotes tissue regeneration, uncontrolled senescence can contribute to disease pathogenesis by presenting the senescence-associated secretory phenotype, in which molecules such as proinflammatory cytokines, matrix metalloproteases, and reactive oxygen species are released into tissue microenvironments. This review will address and critically evaluate the current literature on the role of cellular senescence in hypertension, with particular emphasis on cells types that mediate and modulate vascular function and structure.

Keywords: blood pressure; cellular senescence; hypertension; vascular aging.

Figure 1.

Relative vascular age is accelerated in hypertension. For any given chronological age, a hypertensive patient or animal has an increased vascular age, compared with an age-matched normotensive control. The definition of vascular age encompasses a broad range of phenotypes that can refined into taxonomies such as hypercontractility, stiffening and remodeling, and inflammation and oxidative stress.

Figure 2.

The senescence-associated secretory phenotype from endothelial cells and vascular smooth muscle cells, as well as T cells, fibroblasts, and perivascular adipose tissue (PVAT) synergize to cause vascular wall inflammation and dysfunction, driving the development and/or maintenance of hypertension.

Figure 3.

Autophagy is able to prevent the aged phenotype in endothelial cells. Efficient degradation of dysfunctional organelles and misfolded protein aggregates prevents their accumulation and the induction of oxidative stress, which subsequently reduces nitric oxide bioavailability. Inefficient recycling of cellular waste occurs in both chronological aging and premature aging associated with cardiovascular diseases. Abbreviations: ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype.

Figure 4.

Our current understanding of senescence in hypertension-associated vascular aging, beyond phenotypic recognition, is far from complete. Most of the literature indicates a pressure-dependent association between increased cellular senescence and hypertension. However, there are no current studies demonstrating whether senescence can mediate increases in blood pressure, nor if removal of senescent cells (senolytic therapy) can lower blood pressure and improve vascular function in arteries from hypertensive animals.