MECHANISMS OF RESISTANCE ARTERY STRUCTURAL REMODELING IN HYPERTENSION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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，是导致血管并发症患病率、发病率和死亡率增加的原因。以往的研究表明，高血压患者和动物模型的阻力动脉形态学改变。然而，在体内信号通路有助于血管结构重塑高血压知之甚少，特别是在阻力动脉（RA）。初步数据显示，增加胶原蛋白1型含量，动脉僵硬度和富营养化结构重塑诱导RA血管紧张素II（ANG II）依赖性高血压小鼠。这些RA形态学变化与氧化应激增加、抑制性I κ B蛋白（IKB）磷酸化、p50/p65核因子κ B（NF κ B）磷酸化和易位至细胞核、α-v-β-3-整联蛋白脱落和TGF β 1表达相关。基于这些发现，我们假设升高的氧化应激激活NF κ B通路，导致avb 3-整联蛋白脱落和/或TGF β 1表达和生物活性增加，从而诱导1型胶原异常积聚，导致ANG II依赖性高血压小鼠RA的结构壁重塑和刚度增加。这项建议的目的是： 1)证明ANG II依赖性高血压小鼠RA的氧化应激依赖性NF κ B途径激活增强决定了1型胶原含量、硬度和富营养化重塑诱导的增加。在这个目标中，我们将确定氧化应激是上游信号，激活NF κ B通路负责从ANG II依赖性高血压小鼠RA的形态学变化。 2)描述增强的α-v β-3-整合素脱落和TGF β 1表达对ANG II依赖性高血压小鼠1型胶原含量和硬度增加以及RA的富营养化重塑诱导的作用。在这个目标中，我们将确定α-v-β-3-整联蛋白和TGF β的作用，下游信号的氧化应力和NF κ B，调节胶原1型周转，结构重塑和僵硬的阻力动脉血管紧张素II依赖性高血压小鼠。采用各种技术的方法  药理学、分子生物学“体内腺病毒-siRNA介导的递送”和血管重塑的评估将用于实现本研究的完成。

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.