Hypertension is one of the most common age associated chronic disorders in human and affects more than 1 billion people worldwide. Despite intense research efforts over several decades, there is still no consensus on what are the primary causes of this disorder and its treatment is considered mandatory. It has been widely accepted that the increase in blood pressure with advancing age is mostly consistent with aortic stiffness, however, little is known about mechanisms. Most prior work has focused on the extracellular matrix (ECM) or endothelial control, our previous study and Preliminary Data revealed that aortic vascular smooth muscle cells (VSMCs) stiffness also contributes to the increase aortic stiffness in both aging and hypertension. The parent grant, which focuses on young hypertensive adults, presents a novel concept that a key mechanism for hypertension may reside in VSMC. In this revision application, we will extend this new concept to aged animal models to study the influence of age on vascular changes and the development of hypertension, specifically to differentiate the age dependent changes and hypertension dependent changes in aortic VSMC mechanical properties. Our hypothesis of this revision proposal is that age induced alterations of the intrinsic stiffness of VSMCs and VSMC-ECM interaction in the aorta differs from those with HT in young adults and acts as an independent attributor to increased aortic stiffness and subsequently accelerates the development of hypertension in older individuals. The goal of this proposal is to identify the significance of age induced alterations of VSMC in the development of HT in elderly, and to determine potential cellular/molecular mechanisms mediating these changes, which could then be investigated to uncover novel preventive and therapeutic approaches for age related hypertension. By using the same complex experimental systems as proposed in the parent grant that includes whole animal, isolated vessel, reconstituted tissue and the single cell observations, we will test our Hypothesis through two aged hypertensive rat models, spontaneously hypertensive rats and angiotensin induced hypertensive rats, by the following Specific Aims:
In Specific Aim A, we will incorporate a strategy to identify the age dependent changes of aortic VSMC stiffness and VSM- ECM interaction and whether these age induced alterations are independent of the elevated blood pressure.
In Specific Aim B, we will determine the influence of these changes on the development of hypertension in aged animals and the mechanisms involved. If this hypothesis is correct, this study will lead to further investigation o novel therapeutic strategy for age related hypertension, e.g. with pharmaceutical targets agents directed at the level of the VSMC itself, to reduce age induced aortic stiffness and thus prevent the increase of systolic blood pressure and pulse pressure in elderly.

Public Health Relevance

Lay abstract Hypertension is one of the most common age related chronic disorder in human and is a well?established risk factor for stroke and cardiovascular diseases among older people. Less is known about mechanisms involved in the large arteries. A key feature of the current proposal is to determine the alterations occurring in aortic stiffness during aging due to the novel hypothesis, that a key component occurs intrinsic to vascular smooth muscle cells (VSMCs). By using two novel techniques, atomic force microscopy (AFM) and a reconstituted tissue model, we will identify the changes in intrinsic VSMC stiffness during aging and as hypertension develops in aged animals. Once this is demonstrated, it will open up new avenues of therapy for aortic stiffness and hypertension in elderly, i.e., with pharmaceutical targets directed at the level of the VSMC itself.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL115195-04S1
Application #
8959886
Study Section
Special Emphasis Panel (ZHL1-CSR-P (M3))
Program Officer
OH, Youngsuk
Project Start
2012-07-01
Project End
2017-02-28
Budget Start
2015-08-17
Budget End
2016-02-29
Support Year
4
Fiscal Year
2015
Total Cost
$129,481
Indirect Cost
$47,531
Name
Loma Linda University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
Hays, Tristan T; Ma, Ben; Zhou, Ning et al. (2018) Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats. Aging Cell 17:e12748
Leimena, Christiana; Qiu, Hongyu (2018) Non-Coding RNA in the Pathogenesis, Progression and Treatment of Hypertension. Int J Mol Sci 19:
Stoll, Shaunrick; Wang, Charles; Qiu, Hongyu (2018) DNA Methylation and Histone Modification in Hypertension. Int J Mol Sci 19:
Xu, Shiyue; Tao, Jun; Yang, Liu et al. (2018) E2F1 Suppresses Oxidative Metabolism and Endothelial Differentiation of Bone Marrow Progenitor Cells. Circ Res 122:701-711
Fan, Jingjing; Qiu, Lin; Shu, Hongyang et al. (2018) Recombinant frizzled1 protein attenuated cardiac hypertrophy after myocardial infarction via the canonical Wnt signaling pathway. Oncotarget 9:3069-3080
Zhou, Ning; Lee, Jia-Jye; Stoll, Shaunrick et al. (2017) Rho Kinase Regulates Aortic Vascular Smooth Muscle Cell Stiffness Via Actin/SRF/Myocardin in Hypertension. Cell Physiol Biochem 44:701-715
Lizano, Paulo; Rashed, Eman; Stoll, Shaunrick et al. (2017) The valosin-containing protein is a novel mediator of mitochondrial respiration and cell survival in the heart in vivo. Sci Rep 7:46324
Zhou, Ning; Lee, Jia-Jye; Stoll, Shaunrick et al. (2017) Inhibition of SRF/myocardin reduces aortic stiffness by targeting vascular smooth muscle cell stiffening in hypertension. Cardiovasc Res 113:171-182
Zhou, Ning; Ma, Ben; Stoll, Shaunrick et al. (2017) The valosin-containing protein is a novel repressor of cardiomyocyte hypertrophy induced by pressure overload. Aging Cell 16:1168-1179
Zhou, Ning; Stoll, Shaunrick; Qiu, Hongyu (2017) VCP represses pathological cardiac hypertrophy. Aging (Albany NY) 9:2469-2470

Showing the most recent 10 out of 14 publications