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. 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. Previous studies showed mophological changes in resistance arteries from hypertensive patients and animal models. However, in vivo signaling pathways contributing to vascular structural remodeling in hypertension are poorly understood, especially in resistance arteries (RA). Preliminary data show increased collagen type 1 content, artery stiffness and eutrophic structural remodeling induction of RA from angiotensin II (ANG II)- dependent hypertensive mice. Those RA morphological changes are associated with increased oxidative stress, inhibitory IkappaB proteins (IKB) phosphorylation, p50/p65 Nuclear Factor kappa B (NFkB) phosphorylation and translocation to the nucleus, alpha-v-beta-3-integrin shedding, and TGFbeta1 expression. Based on these findings, we hypothesize that elevated oxidative stress activates NFKB pathway leading to increase of avb3-integrin shedding and/or TGFbeta1 expression and bio-activity, which induces abnormal accumulation of collagen type 1 responsible for structural wall remodeling and increased stiffness of RA from ANG II-dependent hypertensive mice. The aims of this proposal are: 1) To demonstrate that increased collagen type 1 content, stiffness, and eutrophic remodeling induction are dictated by enhanced oxidative stress-dependent NFKB pathway activation of RA from ANG II-dependent hypertensive mice. In this aim we will determine that oxidative stress is upstream signaling that activates NFkB pathway responsible for morphological changes of RA from ANG II-dependent hypertensive mice. 2) To delineate the role of enhanced alpha-vbeta-3-integrin shedding and TGFbeta1 expression on increased collagen type 1 content and stiffness, and eutrophic remodeling induction of RA from ANG II dependent hypertensive mice. In this aim we will establish the role of alpha-v-beta-3-integrin and TGFbeta, down stream signaling to oxidatives tress and NFkB, regulating collagen type 1 turnover, structural remodeling and stiffness of resistance arteries from ANG II-dependent hypertensive mice. Approaches employing a variety of technologies  pharmacology, molecular biology "in vivo adenovirus-siRNA mediated delivery" and assessment of vascular remodeling will be used to achive the completion of this study.