It is well known that vascular stiffness increases with aging, and that the effects of aging on arterial stiffness are relatively protected in older women. Although most prior mechanistic work on the effects of aging on vascular regulation and stiffness has been conducted in rodent models, the extent to which these data can be extrapolated to humans is limited by the marked differences in lifespan over which changes in vascular stiffness develop. Studies of gender differences with aging are even more limited in rodents, due to the fact that the estrogen levels never decline even in very old rodents, and they do not go through menopause. It is generally agreed that non-humans primates are the best models to study gender differences with aging, since the changes in hormones and menstruation in old female (OF) monkeys parallel those in older human females. Our previous studies and preliminary data in aging monkeys have demonstrated that the stiffness of the aorta increases with aging and this aging alteration is greater in males than females, and also much greater in the abdominal aorta (AA) vs. the thoracic aorta (TA), which is only partially explained by variance in extracellular matrix (ECM). Here, we will test the novel Hypothesis that intrinsic mechanisms in the vascular smooth muscle cells (VSMCs) as well as alterations in VSMC-ECM interaction also contribute to the increased stiffness of the aorta in older males, particularly the AA, and conversely, contribute to the protection in pre-menopausal females. This Hypothesis is supported by Preliminary Data demonstrating enhanced stiffness of VSMC in culture from old male (OM) aortas and showing that the number of senescent VSMC increases in OM compared to young males (YM), particularly in AA. Specifically, we will test our Hypothesis through two approaches. In the first approach, we will determine how VSMC stiffness and senescence are affected by age and gender using atomic force microscopy (AFM) and also an artificial tissue model. In the second approach, we will determine both in vivo and in vitro how these factors may explain the regional differences in aortic stiffness between TA and AA.

Public Health Relevance

The increase in vascular stiffness is a major health problem for an increasing aging population in the US. This grant is directed at examining mechanisms inherent in this process which ultimately could be approached therapeutically.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102472-04
Application #
8586272
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2010-04-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$487,429
Indirect Cost
$117,238
Name
Rutgers University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
Zhang, Jie; Zhao, Xin; Vatner, Dorothy E et al. (2016) Extracellular Matrix Disarray as a Mechanism for Greater Abdominal Versus Thoracic Aortic Stiffness With Aging in Primates. Arterioscler Thromb Vasc Biol 36:700-6
Vatner, Stephen F (2016) Why So Few New Cardiovascular Drugs Translate to the Clinics. Circ Res 119:714-7
Bravo, Claudio A; Vatner, Dorothy E; Pachon, Ronald et al. (2016) A Food and Drug Administration-Approved Antiviral Agent that Inhibits Adenylyl Cyclase Type 5 Protects the Ischemic Heart Even When Administered after Reperfusion. J Pharmacol Exp Ther 357:331-6
Jose Corbalan, J; Vatner, Dorothy E; Vatner, Stephen F (2016) Myocardial apoptosis in heart disease: does the emperor have clothes? Basic Res Cardiol 111:31
Pachon, Ronald E; Scharf, Bruce A; Vatner, Dorothy E et al. (2015) Best anesthetics for assessing left ventricular systolic function by echocardiography in mice. Am J Physiol Heart Circ Physiol 308:H1525-9
Lee, Grace J; Yan, Lin; Vatner, Dorothy E et al. (2015) Mst1 inhibition rescues β1-adrenergic cardiomyopathy by reducing myocyte necrosis and non-myocyte apoptosis rather than myocyte apoptosis. Basic Res Cardiol 110:7
Ho, David; Zhao, Xin; Yan, Lin et al. (2015) Adenylyl Cyclase Type 5 Deficiency Protects Against Diet-Induced Obesity and Insulin Resistance. Diabetes 64:2636-45
Vatner, Dorothy E; Yan, Lin; Lai, Lo et al. (2015) Type 5 adenylyl cyclase disruption leads to enhanced exercise performance. Aging Cell 14:1075-84
Yuan, Chujun; Yan, Lin; Solanki, Pallavi et al. (2015) Blockade of EMAP II protects cardiac function after chronic myocardial infarction by inducing angiogenesis. J Mol Cell Cardiol 79:224-31
Sehgel, Nancy L; Vatner, Stephen F; Meininger, Gerald A (2015) ""Smooth Muscle Cell Stiffness Syndrome""-Revisiting the Structural Basis of Arterial Stiffness. Front Physiol 6:335

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