Smad2 in vascular smooth muscle homeostasis

Smad2 在血管平滑肌稳态中的作用

基本信息

批准号：
10062643
负责人：
Shiyou Chen
金额：
$ 50.53万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-12 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062643
关键词：
Adult Affect Age Aging American Angiotensin II Arteries Attenuated Baroreflex Basic Science Blood Pressure Blood Vessels Cardiovascular Diseases Cell Aging Cells Central Artery Collagen Core Facility Coronary Arteriosclerosis Data Defect Development Elasticity Elastin Environment Equipment Extracellular Matrix Genetic Genetic Transcription Goals Heart Diseases Heart failure Histologic Homeostasis Human Hypertension Impairment In Vitro Kidney Knockout Mice Knowledge Laboratories Lead Link Liver Lung Mechanics Medial Mediating Molecular Mus Neural Crest Cell Organ Outcome Pharmacology Phenotype Play Positioning Attribute Premature aging syndrome Prevention strategy Prevention therapy Process Production Pulse Pressure Research Resistance development Resistant Hypertension Resources Risk Risk Factors Role Smooth Muscle Myocytes Stroke Structural defect Structure TP53 gene Techniques Testing Therapeutic Tissues Treatment Efficacy Universities Vascular Smooth Muscle aged animal facility arterial stiffness attenuation blood pressure regulation cardiovascular risk factor clinical application gain of function genetic approach in vivo invention loss of function mechanical properties mouse model novel novel strategies novel therapeutics premature pressure programs

项目摘要

Summary/Abstract Aberration of vascular smooth muscle cell (SMC) phenotypes cause structural defects and impaired mechanical properties of artery wall, leading to artery stiffness, which correlates with high blood pressure and is an independent risk factor for the resistant hypertension. It is well-known that arterial wall stiffens with aging. In addition to hypertension, vascular aging is an independent risk factor for cardiovascular diseases including coronary artery disease, stroke and heart failure. However, the factors and mechanisms that control vascular aging, especially SMC aging and artery stiffness, remain largely unknown. Our exciting preliminary data demonstrate that Smad2 plays a critical role in maintaining SMC and vascular homeostasis and blood pressure. SMC-tissue specific deficiency of Smad2 (Smad2sm-/-) in mice causes alterations in elastin and collagen content and structure in the vessel wall, resulting in decreased artery distensibility, increased pulse pressure (indicator of artery stiffness), and increased mean artery pressure. The vascular wall remodeling/stiffness in Smad2 SMC- deficient mice appears to be caused by a premature SMC aging with an elevation in p53 level. In fact, the increase in p53 level along with the decrease in Smad2 expression in artery SMC correlates with the aging in mouse and human. Importantly, the correlation of decreased Smad2 with increased p53 is also closely associated with the onset of hypertension in human. These data strongly support a novel hypothesis that Smad2 maintains vascular homeostasis and blood pressure by inhibiting p53 expression and/or activity in SMC. Using primary culture of SMCs, in vivo Smad2 and p53 SMC-specific knockout mouse models combining with molecular, cellular, histological, and pharmacological approaches, we will 1) test if Smad2 is essential for maintaining the vascular wall elasticity and blood pressure homeostasis; 2) elucidate the mechanism by which Smad2 regulates SMC homeostasis through inhibiting p53 expression/activity; and 3) determine if blockade of p53 attenuates Smad2 deficiency-caused artery stiffness and hypertension. Successful completion of the proposed study will establish a novel mechanism regulating SMC aging and blood pressure homeostasis. It will also allow us to identify potential novel approaches that may be used to develop effective therapeutics for treating aging or artery stiffness-related hypertension.

摘要/摘要血管平滑肌细胞（SMC）表型的像差导致结构缺陷和机械性障碍动脉壁的特性，导致动脉僵硬，这与高血压相关，是抗性高血压的独立危险因素。众所周知，动脉壁随老化而变硬。在除了高血压外，血管衰老是心血管疾病的独立危险因素冠状动脉疾病，中风和心力衰竭。但是，控制血管的因素和机制衰老，尤其是SMC衰老和动脉僵硬，在很大程度上尚不清楚。我们令人兴奋的初步数据证明SMAD2在维持SMC和血管稳态和血压方面起着至关重要的作用。小鼠中Smc-Tissue特异性缺陷（SMAD2SM - / - ）引起弹性蛋白和胶原蛋白含量的改变和血管壁的结构，导致动脉降低，脉压增加（指示器）动脉刚度）和平均动脉压力增加。 SMAD2 SMC-中的血管壁重塑/刚度不足的小鼠似乎是由p53水平升高的过早SMC老化引起的。实际上， p53水平的增加以及动脉SMC中SMAD2表达的降低与衰老相关老鼠和人类。重要的是，SMAD2降低与p53增加的相关性也很紧密与人类高血压发作有关。这些数据强烈支持一个新的假设 SMAD2通过在SMC中抑制p53表达和/或活性来维持血管稳态和血压。使用SMC的一级培养，体内SMAD2和P53 SMC特异性敲除鼠标模型与分子，细胞，组织学和药理学方法，我们将测试SMAD2是否必不可少保持血管壁弹性和血压稳态； 2）阐明该机制 SMAD2通过抑制p53表达/活性来调节SMC稳态； 3）确定是否封锁 p53减弱了SMAD2缺乏引起的动脉僵硬和高血压。成功完成拟议的研究将建立一种调节SMC衰老和血压稳态的新型机制。会还允许我们识别可能用于开发有效治疗的有效治疗剂的潜在新方法衰老或动脉刚度相关的高血压。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nanoparticle endothelial delivery of PGC-1α attenuates hypoxia-induced pulmonary hypertension by attenuating EndoMT-caused vascular wall remodeling.

DOI：
10.1016/j.redox.2022.102524
发表时间：
2022-12
期刊：
REDOX BIOLOGY
影响因子：
11.4
作者：
Cai, Dunpeng;Chen, Shi-You
通讯作者：
Chen, Shi-You

A Novel Mechanism Underlying Inflammatory Smooth Muscle Phenotype in Abdominal Aortic Aneurysm.

DOI：
10.1161/circresaha.121.319374
发表时间：
2021-10-29
期刊：
Circulation research
影响因子：
20.1
作者：
Cai D;Sun C;Zhang G;Que X;Fujise K;Weintraub NL;Chen SY
通讯作者：
Chen SY

Response by Cui et al to Letter Regarding Article, "RGC-32 (Response Gene to Complement 32) Deficiency Protects Endothelial Cells From Inflammation and Attenuates Atherosclerosis".

Cui 等人对有关文章“RGC-32（补体 32 的响应基因）缺乏可保护内皮细胞免受炎症并减轻动脉粥样硬化”的信件的回应。

DOI：
10.1161/atvbaha.118.311146
发表时间：
2018
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Cui,Xiao-Bing;Luan,Jun-Na;Dong,Kun;Chen,Sisi;Wang,Yongyi;Watford,WendyT;Chen,Shi-You
通讯作者：
Chen,Shi-You

ADAR1 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice.

ADAR1 缺陷可防止小鼠高脂饮食引起的肥胖和胰岛素抵抗。