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。 背景和假设： 血管结构改变已被广泛认为是一种重大的健康威胁和心血管疾病的高危因素。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。我们的中心假设是，氧化应激激活NFKB通路，导致α-v-β-3-整合素脱落，TGFbeta-1表达和生物活性增加，从而导致Ang-II依赖高血压小鼠阻力动脉机械性能改变，从而导致结构壁重构。我们将使用肠系膜阻力动脉(MRA)，因为它们是反映血管变化的良好模型，是微血管的代表，负责30%以上的血压控制。 我们有两个具体目标来实现我们的建议： 总体而言，我们的具体目标1集中在氧化应激依赖的NFKB通路激活增强的作用上，该激活导致依赖Ang-II的高血压小鼠MRA的1型胶原含量增加、僵硬和富营养性重塑诱导。为达致这个目标，我们会决定是否： Subaim 1a：用较低的氧化应激治疗Ang-II依赖型高血压小鼠“apocynin或mitoquone(MitoQ：是一种选择性阻断线粒体氧化应激的线粒体靶向抗氧化剂)”，并使用过度表达线粒体MnSOD的小鼠，注入Ang-II以减少Ang-II依赖型高血压小鼠增加的NFKB途径的激活和易位，α-v-β-3-整合素的脱落，TGFbeta-1的表达和生物活性，富营养重塑，1型胶原含量，以及血管紧张素Ⅱ依赖高血压小鼠MRA的僵硬； Subaim 1b：腺病毒介导的IKB或p50/p65 NFKB亚基-siRNA局部感染Ang II依赖的高血压小鼠，局部下调NFKB途径，分别增强或降低α-v-β-3-整合素脱落、TGFβ-1表达、1型胶原含量、僵硬和富营养性重塑诱导； 总体而言，我们的特定目标2旨在确定增强的α-v-β-3-整合素脱落和转化生长因子β-1的表达在血管紧张素Ⅱ依赖型高血压小鼠MRA中增加的1型胶原含量、僵硬和富营养性重塑诱导中的作用。为达致这个目标，我们会确定： 通过腺病毒介导的α-v-β-3-整合素siRNA的传递和使用药物抑制α-v-β-3-整合素的使用，局部感染血管紧张素Ⅱ依赖的高血压小鼠的MRA局部下调α-v-β-3-整合素的表达，减少MRA诱导的转化生长因子β-1生物活性、1型胶原含量、僵硬和富营养性重塑； 2B：通过腺病毒介导的TGFbeta-1-siRNA递送局部感染依赖Ang II的高血压小鼠的MRA局部下调TGFbeta-1，并使用过表达显性阴性TGFbeta-1受体的小鼠输注Ang II逆转MRA增加的1型胶原含量、僵硬和富营养性重塑诱导。

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.