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.

动脉衰老的特征是依赖内皮的扩张（EDD）和大动脉僵硬。内皮是动脉功能的关键调节剂，参与血管张力的控制，一氮氧化物产生和生物利用度，大动脉僵硬，炎症和屏障功能。恶化糖藻是一种与内皮腔表面结合的凝胶状结构，伴随着年龄通过改变血管内皮的这些功能，相关的血管功能障碍。虽然糖脂主要以其在微脉管系统中的作用而闻名，它也影响了中心心血管特征，糖果脂肪核的劣化或表型变化，年龄可能会损害更大的年龄动脉功能。小鼠和人类的微脉管系统中糖脂的厚度降低随着年龄的增长，这似乎伴随着其组成分子的改变。虽然关于透明质酸（HA）的含量，主要糖胺聚糖之一（HA）尚无共识内皮糖脂的成分，整个寿命下降，有表型的证据从高（HMW-HA）转移到低分子量。保持年轻的HMW-HA个人资料的重要性观察到HMW-HA具有抗衰老，血管保护特性，这证明了这一点。在三公顷合酶（HAS）酶，HAS2产生大多数HMW-HA。但是，尽管has2减少已经在具有衰老的非血管组织中报道了基因表达 HAS2表达的老化是有限的。因此，尽管有证据表明糖囊肿的改变。它是组成，哈；负责生产的酶Has2与年龄相关的动脉一致功能障碍，他们的因果角色仍然难以捉摸。在这里，我们将利用内皮特定，功能的损失和增益小鼠模型以阐明has2和ha表型在糖瘤动脉变化中的作用整个小鼠寿命的功能，炎症和渗透性。我们还将审问哈哈的角色受体CD44，这些作用。最后，我们将评估用HMW-HA补充饮食的功效改善动脉功能的这些方面在促进年龄和探索潜在机制方面。结果将阐明与年龄有关的血管功能障碍的新型机制，并证明概念证明用于改善与年龄相关的动脉功能障碍的新治疗方法，该动脉功能障碍很容易翻译为人类。