Fibrinogen-induced vasoconstriction during hypertension

高血压期间纤维蛋白原诱导的血管收缩

• 批准号: 7360319
• 负责人: DAVID LOMINADZE
• 金额: $ 37万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7360319
• 关键词: Acetates; Age; Animals; Attenuated; Big Endothelin; Binding; Blood; Blood Pressure; Cardiovascular system; Cerebrovascular Disorders; Confocal Microscopy; Control Animal; Deoxycorticosterone; Development; Dose; Elevation; Endothelial Cells; Endothelin; Endothelin-1; Endothelium; Enzymes; Exocytosis; Extracellular Signal Regulated Kinases; F-Actin; Fibrinogen; Figs - dietary; Flow Cytometry; Genetic; Genetic Models; Hypertension; Inbred SHR Rats; Inbred WKY Rats; Inflammatory; Integrin alpha5beta1; Integrins; Intercellular adhesion molecule 1; JUN gene; MALDI-TOF Mass Spectrometry; Maintenance; Mediating; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Operative Surgical Procedures; PD-98059; Phosphorylation; Plasma; Production; Protein Kinase; Proteins; Proteome; Proteomics; Rattus; Reporting; Research Personnel; Resolution; Risk Factors; Role; SP600125; Signal Pathway; Signal Transduction; Small Interfering RNA; Sodium Chloride; Sprague-Dawley Rats; Staging; Surface; Time; Transfection; Two-Dimensional Polyacrylamide Gel Electrophoresis; Vascular Endothelium; Week; Weibel-Palade Bodies; animal data; arteriole; base; inhibitor/antagonist; mouse Smc1l1 protein; mouse Smc1l2 protein; novel; programs; receptor; research study; response; salicylhydroxamic acid; stress-activated protein kinase 1; vasoconstriction

DESCRIPTION (provided by applicant): Hypertension is accompanied by an increased content of plasma fibrinogen (Fg). We reported that binding of Fg to the arterial wall causes vasoconstriction, which is mediated by intercellular adhesion molecule-1 (ICAM-1). In addition, blockade of the endothelin type A receptors attenuated Fg-induced vasoconstriction. In our preliminary studies, endothelial binding of Fg enhanced production of endothelin-1 (ET-1). Furthermore, Fg binding to endothelial cells (ECs) resulted in phosphorylation of extracellular signal regulated kinase (ERK). Activation of ICAM-1 and another Fg endothelial receptor, alpha5beta1 integrin, leads to phosphorylation of ERK and c-Jun-NH2-terminal kinase (JNK). Fg-induced vasoconstriction is increased during hypertension, and regulated production of ET-1 results from exocytosis of Weibel-Palade bodies (WPb). We hypothesize that during hypertension, increased Fg binding to endothelial ICAM-1 (and possibly alpha5beta1) induces enhanced exocytosis of WPbs through ERK (and possibly JNK) signaling and results in increased production of ET-1 leading to enhanced vasoconstriction. Based on our finding that Fg binding to ECs changes EC proteome which may be associated with WPb exocytosis, we will determine if these Fg-induced cellular changes are associated with ET-1 release, and therefore with vasoconstriction. The specific aims of the proposed study are: 1) To evaluate Fg binding to ICAM-1, the resultant production of ET-1, and subsequent vasoconstriction during hypertension; 2) To determine the signaling pathway (ERK- and/or JNK-involved) for Fg-induced ET-1 production and the elevated vasoconstriction during hypertension; and 3) To determine the functional role of EC proteins altered by Fg binding in Fg-induced exocytosis of WPbs during hypertension. Hypertension-induced enhanced Fg binding to endothelial ICAM-1 (and alpha5beta1), the role of ERK (and JNK) signaling and the role of proteins altered by Fg binding to ECs in increased exocytosis of WPbs and production of ET-1, which causes enhanced vasoconstriction, will be determined. Genetic (SHR) and non-genetic (DOCA-salt) rat hypertension models will be studied at early and established stages of hypertension to identify changes associated with the development and maintenance of hypertension. This study will delineate mechanisms of Fg-regulated production of ET-1 and the resultant increased vasoconstriction that exacerbates microcirculatory complications during hypertension.

描述（申请人提供）：高血压伴随血浆纤维蛋白原（Fg）含量增加。我们报道了 Fg 与动脉壁的结合引起血管收缩，这是由细胞间粘附分子 1 (ICAM-1) 介导的。此外，阻断 A 型内皮素受体可减弱 Fg 诱导的血管收缩。在我们的初步研究中，Fg 的内皮结合增强了内皮素-1 (ET-1) 的产生。此外，Fg 与内皮细胞 (EC) 结合导致细胞外信号调节激酶 (ERK) 磷酸化。 ICAM-1 和另一种 Fg 内皮受体 α5β1 整合素的激活会导致 ERK 和 c-Jun-NH2 末端激酶 (JNK) 磷酸化。高血压期间 Fg 诱导的血管收缩增加，Weibel-Palade 小体 (WPb) 的胞吐作用导致 ET-1 的产生受到调节。我们推测，在高血压期间，Fg 与内皮 ICAM-1（可能还有 α5β1）结合的增加会通过 ERK（可能还有 JNK）信号传导诱导 WPb 的胞吐作用增强，并导致 ET-1 的产生增加，从而增强血管收缩。基于我们的发现，Fg 与 EC 结合会改变 EC 蛋白质组，这可能与 WPb 胞吐作用有关，我们将确定这些 Fg 诱导的细胞变化是否与 ET-1 释放相关，从而与血管收缩相关。本研究的具体目的是： 1) 评估 Fg 与 ICAM-1 的结合、由此产生的 ET-1 以及高血压期间随后的血管收缩； 2) 确定Fg诱导的ET-1产生和高血压期间血管收缩升高的信号通路（ERK和/或JNK参与）； 3) 确定在高血压期间Fg 诱导的WPb 胞吐作用中Fg 结合改变的EC 蛋白的功能作用。将确定高血压诱导的 Fg 与内皮 ICAM-1（和 alpha5beta1）结合增强、ERK（和 JNK）信号传导的作用以及 Fg 与 EC 结合而改变的蛋白质在增加 WPb 胞吐作用和 ET-1 产生（从而导致血管收缩增强）中的作用。将在高血压的早期和已建立阶段研究遗传（SHR）和非遗传（DOCA-盐）大鼠高血压模型，以确定与高血压发展和维持相关的变化。这项研究将阐明 Fg 调节 ET-1 产生的机制，以及由此产生的血管收缩增加，从而加剧高血压期间的微循环并发症。