Vascular Response to Hemmorhage in Portal Hyprtension

描述（由申请人提供）：门静脉的多变表现 高血压（PHT）每年导致超过10万美国人死亡， 不成比例地针对少数群体和妇女，因为他们的 易患肝病。出血性休克是最常见的致命性 门静脉高压症并发症，患者可耐受大出血 很糟糕目前的治疗方式实际上可能会加重潜在的 出血的原因，由于对发病机制的认识不足， 异常的生理机能我们的实验室在阐明 对PHT的发展至关重要，包括确定 内脏血流量增加的假定介质（NO、PGI 2、血管紧张素 [ANGII]、内皮素[ET]和PHT中改变的跨膜信号传导， 是血管对出血反应改变的基础这项建议旨在 确定机械力（增加的流量， 压力和应变），以及内脏血增加的假定介质 血流量（NO，PGI 2，ANGII，ET），以及对出血的异常血管反应， PHT。我们的中心假设是管腔内机械力的变化 （压力和剪切应力）增加血管舒张的内皮表达 长期调节升压激素受体跨膜的物质 PHT中的信号传导和血管结构变化决定了异常的 充血血管对出血和复苏的反应性。我们 将使用PHT伴和不伴肝硬化的体内模型（胆管结扎 [BDL]和部分门静脉结扎[PVL]），在野生型和iNOS、eNOS、考克斯 1，考克斯2敲除小鼠，结合体外模型灌注 跨毛细血管内皮细胞（EC）和血管平滑肌细胞（VSMC） 共培养系统和Flexercell应变系统（模拟体内细胞培养）。 血管结构和流动、压力和应变的机械力）。我们 将评估机械力对EC一氧化氮合酶的影响 (NOS)和环氧合酶（考克斯）表达/活性与VSMC升压激素 受体（血管紧张素Ⅱ，内皮素）表达和跨膜信号转导和血管平滑肌细胞 扩散和迁移。我们将确定：1）内皮细胞的变化 NOS和考克斯的表达响应于流量、压力或应变的变化; 2)VSMC受体和跨膜信号传导的变化以及 增殖和迁移的改变; 3）如果剪切、压力或应变 诱导的变化受肝脏疾病存在与否的调节 （肝硬化）;和4）如果机械力诱导EC血管活性变化， 物质表达或VSMC变化导致血管对 出血和休克总之，我们将确定障碍物的作用， 门脉血流以及机械力和肝硬化对门脉血流的影响 对出血和复苏的异常血管反应。这些实验 将为我们理解PHT提供重要的新信息， 并直接导致有效的治疗方案。

DESCRIPTION (Provided by Applicant): The protean manifestations of portal hypertension (PHT) lead to the deaths of over 100,000 Americans each year, and disproportionately target minorities and women due to their greater susceptibility to liver disease. Hemorrhagic shock is the most common lethal complication of portal hypertension where patients tolerate massive hemorrhage poorly. Current treatment modalities may actually aggravate the underlying cause of bleeding, due to the poor understanding of the pathogenesis of the abnormal physiology. Our lab has been instrumental in elucidating the factors critical to the development of PHT, including the identification of the putative mediators of increased splanchnic blood flow (NO, PGI2, angiotensin [ANGII], endothelin [ET), and an altered transmembrane signaling in PHT that underlies the altered vascular response to hemorrhage. This proposal seeks to determine the relationship between the mechanical forces (increased flow, pressure and strain), and the putative mediators of increased splanchnic blood flow (NO, PGI2, ANGII, ET), and the abnormal vascular response to hemorrhage in PHT. Our central hypothesis is that changes in intraluminal mechanical forces (pressure and shear stress) increase endothelial expression of vasodilatory substances that chronically regulate pressor hormone receptor transmembrane signaling and vessel structural changes in PHT that determines the abnormal responsiveness of the hyperemic vasculature to hemorrhage and resuscitation. We will use in vivo models of PHT with and without cirrhosis (bile duct ligated [BDL] and partial portal vein ligated [PVL]) in wild type and iNOS, eNOS, COX 1, COX 2 knockout mice, in conjunction with in vitro models of perfused transcapillary endothelial cell (EC) and vascular smooth muscle cell (VSMC) co-culture system, and the Flexercell Strain System (mimicking the in vivo vascular architecture and mechanical forces of flow, pressure and strain). We will evaluate the effect of mechanical force upon EC nitric oxide synthase (NOS) and cyclooxygenase (COX) expression/activity and VSMC pressor hormone receptor (ANGII, ET) expression and transmembrane signaling and VSMC proliferation and migration. We will determine: 1) changes in endothelial expression of NOS and COX in response to changes in flow, pressure, or strain; 2) changes in VSMC receptor and transmembrane signal transduction as well as alterations in proliferation and migration; 3) if shear, pressure, or strain induced alterations are modulated by the presence or absence of liver disease (cirrhosis); and 4) if mechanical force induced changes in EC vasoactive substance expression or VSMC changes result in abnormal vascular response to hemorrhage and shock. In summary, we will determine the role of obstruction to portal flow and the influence of mechanical forces and cirrhosis upon the abnormal vascular response to hemorrhage and resuscitation. These experiments will provide significant new information central to our understanding of PHT, and lead directly to effective treatment programs.