Integrative Mechanisms of Vascular Aging

点击翻译按钮获取中文摘要

Arterial aging is characterized by diminished endothelium dependent dilation (EDD) and large artery stiffening. The endothelium is a critical modulator of arterial function participating in the control of vascular tone, nitric oxide production and bioavailability, large artery stiffening, inflammation, and barrier function. Deterioration of the glycocalyx, a gel-like structure bound to the luminal surface of the endothelium, is accompanied by age- associated vascular dysfunction by altering these functions of the vascular endothelium. Although the glycocalyx is primarily known for its role in the microvasculature, it also impacts central cardiovascular features, and deterioration or phenotypic changes in the glycocalyx with advancing age that likely impair larger arterial function. The thickness of the glycocalyx decreases in the microvasculature of both mice and humans with advancing age and this appears to be accompanied by alterations in its constituent molecules. Although there is no consensus on whether the content of hyaluronan (HA), one of the primary glycosaminoglycan components of the endothelial glycocalyx, decreases across the lifespan, there is evidence of a phenotypic shift from high (HMW-HA) to low molecular weight. The importance of maintaining a youthful, HMW-HA, profile is demonstrated by observations that HMW-HA has anti-aging, vasoprotective properties. Among the three HA synthase (HAS) enzymes, HAS2 produces the majority of HMW-HA. However, although reductions in HAS2 gene expression have been reported in non-vascular tissues with aging, arterial data concerning the effects of aging on HAS2 expression are limited. Thus, despite evidence suggesting that alterations in the glycocalyx; its constituent, HA; and the enzyme responsible for its production, HAS2, are coincident with age-related arterial dysfunction, their causal role remains elusive. Here, we will utilize endothelial specific, loss and gain of function mouse models to elucidate the role of HAS2 and HA phenotype in alterations in the glycocalyx, arterial function, inflammation, and permeability across the lifespan of mice. We will also interrogate the role of a HA receptor, CD44, in these effects. Last, we will assess the efficacy of dietary supplementation with HMW-HA to improve these aspects of arterial function in advancing age and explore underlying mechanisms. The results will elucidate novel mechanisms of age-related vascular dysfunction as well as demonstrate proof-of-concept for a new therapeutic to ameliorate age-associated arterial dysfunction that is easily translatable to humans.