MECHANISMS OF RESISTANCE ARTERY STRUCTURAL REMODELING IN HYPERTENSION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background and hypothesis: Alteration of vascular structure has been largely accepted as a significant health threat and high risk factor in cardiovascular disease. Hypertension, the most important risk factor for cardiovascular disease, is at epidemic levels in the UNITED STATES being responsible for increased prevalence of vascular complications, and morbidity and mortality. Our central hypothesis is that elevated oxidative stress activates NFKB pathway leading to alpha-v-beta-3-integrin shedding and TGFbeta-1 expression and bio-activity increase, which induces structural wall remodeling responsible for altered mechanical properties of resistance artery from Ang-II-dependent hypertensive mice. We will use mesenteric resistance arteries (MRA) because they are good model reflecting changes in vessels, representative of microvessels and responsible for more than 30% blood pressure control. We have two Specific Aims to accomplish our proposal: Overall, our Specific Aim 1 is focused on the role of the enhanced oxidative stress-dependent NFKB pathway activation responsible for the increased collagen type 1 content, stiffness, and eutrophic remodeling induction of MRA from Ang-II-dependent hypertensive mice. To achieve this aim, we will determine if: Subaim 1a: treatment of Ang-II-dependent hypertensive mice with lower oxidative stress "apocynin or mitoquinone (MitoQ: is a mitochondria-targeted antioxidant that selectively blocks mitochondrial oxidative stress)", and the use of mice that over-express mitochondrial MnSOD infused with Ang-II to reduce the increased NFKB pathway activation and translocation, alpha-v-beta-3-integrin shedding, TGFbeta-1 expression and bioactivity, eutrophic remodeling, collagen type 1 content, and stiffness of MRA from Ang-II-dependent hypertensive mice; Subaim 1b: local down regulation of NFKB pathway by local infection of MRA from ANG II-dependent hypertensive mice with adenovirus-mediated IKB or p50/p65 NFKB subunits-siRNA delivery potentiates or reduces, respectively, the increased alpha-v-beta-3-integrin shedding, TGFbeta-1 expression, collagen type 1 content, stiffness and eutrophic remodeling induction; Overall, our Specific Aim 2 is directed to determine the role of enhanced alpha-v-beta-3-integrin shedding and TGFbeta-1 expression on increased collagen type 1 content, stiffness, and eutrophic remodeling induction in MRA from Ang-II-dependent hypertensive mice. To accomplish this aim, we will ascertain if: 2a: local down regulation of alpha-v-beta-3-integrin by local infection of MRA from ANG II-dependent hypertensive mice with adenovirus-mediated alpha-v-beta-3-integrin-siRNA delivery and the use of pharmacological inhibition of alpha-v-beta-3-integrin reduce the increased TGF beta-1 bioactivity, collagen type 1 content, stiffness, and eutrophic remodeling induction of MRA from; 2b: local down regulation of TGFbeta-1 by local infection of MRA from ANG II-dependent hypertensive mice with adenovirus-mediated TGFbeta-1-siRNA delivery, and the use of mice overexpressing dominant negative TGFbeta-1 receptor infused with ANG II reverse the increased collagen type 1 content, stiffness, and eutrophic remodeling induction of MRA.