An increase in vascular stiffness is a fundamental component of hypertension, however, little is known about mechanisms. Most prior work has focused on the extracellular matrix or endothelial control. Our Preliminary Data revealed not only that aortic vascular smooth muscle cells (VSMCs) stiffness increases but also that the oscillation of elasticity changes in spontaneously hypertensive rats compared to normotensive Wistar-Kyoto (WKY) rats. The central hypothesis of this proposal is that a significant component of the increased large artery stiffness in hypertension also is intrinsic to isolated VSMCs. The goal of this proposal is to establish that isolated VSMC stiffness increases in hypertension and to determine potential cellular/molecular mechanisms mediating these changes, which could then be investigated to uncover novel therapeutic approaches for hypertension. We will test our Hypothesis in this proposal with complex model systems that includes whole animal, isolated vessel, reconstituted tissue and the single cell observations with three different hypertensive animal models by the following strategies: First, in Hypothesis 1, we will incorporate a strategy to test whether intrinsic VSMC stiffness contributes to the development of hypertension. We will determine the correlation between increased peripheral vascular resistance and increased aortic vascular stiffness (Specific Aim 1-1);the alterations of VSMC stiffness and dynamic oscillation in vitro (Specific Aim 1-2);the correlation between contractile status and stiffness o VSMC and aortic VSMC (Specific Aim 1-3)and small resistance arteries(Specific Aim 1-4);finally we will use a selective smooth muscle myosin inhibitor to determine whether the contribution of intrinsic elasticity of VSMCs to the development of hypertension is independent from other factors (Specific Aim 1-5). Secondly, in Hypothesis 2, we will investigate the cellular/molecular mechanisms involved in the alteration of aortic VSMC stiffness in the development of hypertension (Specific Aim 2-1) and the potential regulative mechanism related to the Rho- kinase (Specific Aim 2-2). We will also elucidate the mechanism of Rho-kinase inhibitor as one of potential pharmaceutical targets of hypertension therapy directed at the level of the VSMC itself (Specific Aim 2-3), which open up new avenues for therapy of aortic stiffness and hypertension.
Hypertension is one of the most common cardiovascular diseases which eventually results in heart or renal failure or stroke. 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 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 as hypertension develops. Once this is demonstrated, it will open up new avenues of therapy for aortic stiffness and hypertension, i.e., with pharmaceutical targets directed at the level of the VSMC itself.
|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|
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