Integrative Mechanisms of Vascular Aging

血管老化的综合机制

基本信息

批准号：
10608880
负责人：
Anthony John Donato
金额：
$ 47.28万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608880
关键词：
Age Aging Aorta Arteries Attenuated Binding Biological Availability Blocking Antibodies Blood Vessels C57BL/6 Mouse CD44 Antigens CD44 gene Cardiovascular Diseases Cardiovascular system Cause of Death Cell Communication Cell physiology Characteristics Clustered Regularly Interspaced Short Palindromic Repeats Complex Consensus Custom Data Deterioration Development Diet Dietary Supplementation Elasticity Elderly Endothelial Cells Endothelium Enzymes Event Female Functional disorder Gel Gene Expression Genetic Glycocalyx Glycosaminoglycans Human Hyaluronan Immune Impairment Inflammation Knock-out Ligands Longevity Maintenance Measures Mediating Modeling Molecular Weight Mus Nitric Oxide Outcome Outcome Assessment Outcome Measure Permeability Phenotype Play Production Property Protein Isoforms Reporting Role Signal Transduction Structure Supplementation Surface Tamoxifen Therapeutic Uses Thick Tissues Vascular Diseases Vascular Endothelium Vasodilation Vasodilator Agents age effect age related anti aging arterial stiffness efficacy evaluation endothelial dysfunction gain of function hyaluronan synthase 1 improved knock-down loss of function male middle age mouse model novel novel therapeutics overexpression receptor

项目摘要

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.

动脉老化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关键调节剂，参与控制血管张力、硝酸盐氧化物的产生和生物利用度、大动脉硬化、炎症和屏障功能。恶化糖萼是一种与内皮细胞腔表面结合的凝胶状结构，伴随着年龄增长通过改变血管内皮的这些功能来治疗相关的血管功能障碍。虽然糖萼主要因其在微血管中的作用而闻名，它还影响中枢心血管随着年龄的增长，糖萼的特征、恶化或表型变化可能会损害更大的动脉功能。小鼠和人类微血管中糖萼的厚度均减少随着年龄的增长，这似乎伴随着其组成分子的变化。虽然对于主要糖胺聚糖之一的透明质酸 (HA) 的含量是否存在共识尚未达成共识内皮糖萼的成分在整个生命周期中减少，有证据表明表型从高分子量（HMW-HA）转向低分子量。保持年轻的 HMW-HA 形象的重要性观察结果表明，HMW-HA 具有抗衰老、血管保护特性。三个医管局当中合酶 (HAS) 中，HAS2 产生大部分 HMW-HA。然而，尽管 HAS2 减少据报道，非血管组织中的基因表达与衰老、动脉数据有关衰老对HAS2表达的影响是有限的。因此，尽管有证据表明糖萼发生了变化；它是成分，HA；负责其产生的酶 HAS2 与年龄相关的动脉一致功能障碍，其因果作用仍然难以捉摸。在这里，我们将利用内皮特异性、功能丧失和获得小鼠模型阐明 HAS2 和 HA 表型在糖萼、动脉变化中的作用小鼠整个生命周期的功能、炎症和渗透性。我们也会询问医管局的角色 CD44受体，在这些作用中。最后，我们将评估膳食补充剂 HMW-HA 的功效改善老龄化过程中动脉功能的这些方面并探索潜在机制。结果将阐明与年龄相关的血管功能障碍的新机制并证明概念寻找一种可轻松应用于人类的新疗法，以改善与年龄相关的动脉功能障碍。