Integrative Mechanisms of Vascular Aging

动脉衰老的特征是内皮依赖性扩张(EDD)减弱和大动脉硬化。 内皮细胞是动脉功能的重要调节者，参与血管张力、一氧化氮的控制 氧化物的产生和生物利用度、大动脉硬化、炎症和屏障功能。劣化 糖萼是一种凝胶状结构，结合在内皮细胞的管腔表面，伴随着年龄- 通过改变血管内皮细胞的这些功能而导致的相关血管功能障碍。尽管 糖萼主要因其在微血管系统中的作用而为人所知，它也影响中枢心血管 随着年龄的增长，糖萼的特征、退化或表型变化可能会损害较大的 动脉功能。在小鼠和人的微血管系统中，糖萼的厚度都减少了 随着年龄的增长，这似乎伴随着其组成分子的变化。虽然 透明质酸(HA)是一种主要的糖胺多聚糖，对于其含量是否存在共识，目前尚无共识 随着寿命的延长，内皮细胞糖萼的成分减少，有证据表明表型 从高分子量(HMW-HA)向低分子量转变。保持年轻的HMW-HA形象的重要性 观察表明，HMW-HA具有抗衰老、血管保护作用。三间医管局 合成酶(HAS)，HAS2产生大部分HMW-HA。然而，尽管HAS2的减少 随着年龄的增长，非血管组织中的基因表达已经被报道，关于血管紧张素转换酶的影响的动脉数据 增龄对HAS2表达的影响有限。因此，尽管有证据表明糖萼的变化；但它的 其组成成分HA和负责其产生的酶HAS2与年龄相关的动脉吻合 功能障碍，它们的因果作用仍然难以捉摸。在这里，我们将利用内皮细胞的特异性、功能的丧失和获得 小鼠模型阐明HAS2和HA表型在糖萼、动脉粥样硬化中的作用 小鼠一生中的功能、炎症和渗透性。我们还将审问房委会的角色 受体，CD44，在这些作用中。最后，我们将评估膳食补充HMW-HA的效果 在增龄过程中改善这些方面的动脉功能，并探索潜在的机制。结果是 将阐明与年龄相关的血管功能障碍的新机制，并展示概念验证 寻找一种新的疗法来改善与年龄相关的动脉功能障碍，这种疗法很容易翻译给人类。

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.