MECHANISMS OF RESISTANCE ARTERY STRUCTURAL REMODELING IN HYPERTENSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 高血压是心血管疾病最重要的危险因素，在美国处于流行水平，是血管并发症患病率、发病率和死亡率增加的原因。以前的研究表明，高血压患者和动物模型的阻力动脉发生了形态变化。然而，对高血压血管结构重塑的体内信号通路了解甚少，尤其是在阻力动脉(RA)。初步数据显示，血管紧张素II(Ang II)依赖型高血压小鼠RA的I型胶原含量、动脉僵硬和富营养性结构重建诱导增加。这些RA的形态变化与氧化应激增加、抑制IkappaB蛋白(IKB)磷酸化、p50/p65核因子kappaB(NFkB)磷酸化和转位、α-v-β-3-整合素脱落和TGFbeta1表达有关。基于这些发现，我们假设氧化应激激活NFKB通路，导致avb3-整合素脱落和/或TGFbeta1表达和生物活性增加，从而导致1型胶原的异常积聚，导致Ang II依赖高血压小鼠的结构壁重建和RA僵硬增加。这项建议的目的是： 1)从Ang II依赖型高血压小鼠的RA氧化应激依赖的NFKB通路激活的增强来证明I型胶原含量增加、僵硬和富营养性重塑的诱导。为此，我们将确定氧化应激是上游信号，激活NFkB通路，导致Ang II依赖型高血压小鼠RA的形态变化。 2)探讨α-vbeta-3-整合素脱落和TGFbeta1表达增强在血管紧张素Ⅱ依赖性高血压小鼠RA中I型胶原含量和硬度增加以及诱导RA富营养性重塑中的作用。在这一目标中，我们将确定α-v-β-3-整合素和转化生长因子β的作用，下游信号转导到氧化剂STRESS和NFkB，调节血管紧张素Ⅱ依赖型高血压小鼠的1型胶原转化、结构重塑和阻力动脉的僵硬。采用多种技术的方法，包括药理学、分子生物学、“在体腺病毒-siRNA介导的传递”和血管重塑的评估，将被用于完成这项研究。

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.