Effects of aging on angiogenesis

Abstract

Aging is a dominant risk factor for most forms of cardiovascular disease. Impaired angiogenesis and endothelial dysfunction likely contribute to the increased prevalence of both cardiovascular diseases and their adverse sequelae in the elderly. Angiogenesis is both an essential adaptive response to physiological stress and an endogenous repair mechanism after ischemic injury. In addition, induction of angiogenesis is a promising therapeutic approach for ischemic diseases. For these reasons, understanding the basis of age-related impairment of angiogenesis and endothelial function has important implications for understanding and managing cardiovascular disease. In this review, we discuss the molecular mechanisms that contribute to impaired angiogenesis in the elderly and potential therapeutic approaches to improving vascular function and angiogenesis in aging patients.

Figure 1

Overview of Angiogenic Pathways. Some of the major pathways regulating angiogenesis are depicted. In response to a range of stimuli (such as hypoxia and exercise), tissue responded with enhanced expression of secreted, angiogenic peptides such as VEGF (intended here to represent the broader family of such peptides). Pathways that are important in aging (such as sirtuins, p16/p19, and telomerase) have important effects on both these angiogenic pathways. The angiogenic peptides act through eNOS-dependent and –independent mechanisms to regulate endothelial growth and chemotaxis to enhance angiogenesis. NO itself regulates some of these processes while also acting on vascular smooth muscle cells to modulate vascular tone and consequently flow which also affects vessel development

Figure 2

A schematic representation of normal vascular function and angiogenesis and the effects of aging.) Normal capillary density in young individuals allows dynamic regulation of blood flow according to metabolic needs of the tissue. Aging impairs capillary density as well as flow-mediated vasodilation and eNOS function.) Hypoxia stimulates Hif-1α activation and production of growth factors in ischemic cells. Secreted growth factors form a gradient in ischemic tissues guiding growth of blood vessels. Angiogenic growth factors activate endothelial cells and stimulate production of growth factors, their receptors, matrix metalloproteinases that degrade the capillary basement membrane and extracellular matrix and expression of integrins. VEGF upregulates and activates eNOS leading to vasodilation. Aging impairs HIF1α activation, growth factor production and inhibits matrix metalloproteinase activity by increasing Tissue Inhibitor of Metalloproteinase (TIMP) expression. ROS stress in aging endothelial cells impairs eNOS activation and bioavailability of NO is reduced due to uncoupling of eNOS function and increased destruction of NO.) Endothelial cells proliferate, migrate into extracellular matrix and form vascular structures. Senescent endothelial cells have lower proliferative capacity due to eNOS deficiency, decreased telomerase activity and DNA damage, reduced growth factor production and oxidative stress. Endothelial migration is impaired leading to reduced tube formation. Bone marrow-derived and tissue resident progenitor cells promote angiogenesis by secreting growth factors and by directly incorporating into forming blood vessels. Aging impairs recruitment of progenitor cells from bone marrow and their survival and function. Pericyte function is impaired in aging tissues destabilizing vessels.

Figure 3

eNOS has a central role in vascular function and angiogenesis. Shear stress, VEGF, estrogen and increase in intracellular calcium concentration stimulate eNOS activation in healthy endothelial cells. eNOS plays multiple functions in blood vessel function and angiogenesis. eNOS is an important mediator of endothelial cell proliferation, recruitment and function of endothelial progenitor cells, mediator of endothelium-dependent vasorelaxation and inhibitor of platelet aggregation. In addition, eNOS has been shown to play a role in induction of telomerase activity and mitochondrial biogenesis. Aging reduces eNOS expression, activation and NO bioavailability. Reduced telomerase activity, SIRT1 expression, reduced estrogen stimulation and oxidative stress contribute to eNOS dysfunction.