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.

Public Health Relevance

Hypertension is a leading risk factor for heart disease and stroke. Nearly 78 million American adults have hypertension, and almost two-thirds of those are age 55 and older. Stiffening of blood vessels occurs with aging and is linked with the increased risk of hypertension. In this application, a combination of molecular, cellular, pharmacological, and genetic approaches with gain-of-function and loss-of-function studies will be used to establish a novel mechanism by which alterations in vascular smooth muscle homeostasis contributes to the altered vascular mechanics, which may lead to new strategies for prevention and therapy of hypertension, particularly the resistant hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL135854-02
Application #
9395944
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Olive, Michelle
Project Start
2016-12-12
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Georgia
Department
Physiology
Type
Schools of Veterinary Medicine
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Li, Feifei; Guo, Xia; Chen, Shi-You (2017) Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis. Front Cardiovasc Med 4:32
Guo, Xia; Li, Feifei; Xu, Zaiyan et al. (2017) DOCK2 deficiency mitigates HFD-induced obesity by reducing adipose tissue inflammation and increasing energy expenditure. J Lipid Res 58:1777-1784
Tang, Rui; Zhang, Gui; Wang, Yung-Chun et al. (2017) The long non-coding RNA GAS5 regulates transforming growth factor ? (TGF-?)-induced smooth muscle cell differentiation via RNA Smad-binding elements. J Biol Chem 292:14270-14278
Shi, Ning; Li, Chen-Xiao; Cui, Xiao-Bing et al. (2017) Olfactomedin 2 Regulates Smooth Muscle Phenotypic Modulation and Vascular Remodeling Through Mediating Runt-Related Transcription Factor 2 Binding to Serum Response Factor. Arterioscler Thromb Vasc Biol 37:446-454
Wang, Yung-Chun; Cui, Xiao-Bing; Chuang, Ya-Hui et al. (2017) Janus Kinase 3, a Novel Regulator for Smooth Muscle Proliferation and Vascular Remodeling. Arterioscler Thromb Vasc Biol 37:1352-1360