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: 7209670
• 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 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209670
• 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（由申请人提供）：高血压伴随着血浆纤维蛋白原（FG）的含量增加。我们报告说，FG与动脉壁的结合会导致血管收缩，这是由细胞间粘附分子-1（ICAM-1）介导的。此外，内皮素A型受体的阻断会减弱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）的结合导致细胞外信号调节激酶（ERK）的磷酸化。 ICAM-1和另一种FG内皮受体的激活Alpha5beta1整合素会导致ERK和C-JUN-NH2-末端激酶（JNK）的磷酸化。在高血压期间，FG诱导的血管收缩增加，ET-1的产生由微生甲虫体（WPB）产生。我们假设在高血压期间，FG与内皮ICAM-1（可能是α5BETA1）的FG结合增加会诱导通过ERK（以及可能是JNK）信号传导的WPB的胞吞作用增强，并导致ET-1的产生增加，从而增加了ET-1的产生。根据我们的发现，FG与ECS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释放有关，因此与血管收缩有关。拟议的研究的具体目的是：1）评估FG与ICAM-1的结合，由ET-1的产生产生以及随后在高血压期间的血管收缩； 2）确定用于FG诱导的ET-1产生的信号通路（ERK-和/或JNK涉及的）和高血压期间的血管收缩升高； 3）确定在高血压期间，FG结合在FG诱导的WPBS中的FG结合改变的EC蛋白的功能作用。高血压诱导的FG与内皮ICAM-1（和α5BETA1）的结合，ERK（和JNK）信号的作用以及FG与ECS与ECS结合而改变的蛋白质的作用在增加的ET-1中与ET的产生增加，这会导致增强的血管肿胀，从而确定增强的血压张力。遗传（SHR）和非遗传（DOCA-SALT）大鼠高血压模型将在早期和建立的高血压阶段进行研究，以确定与高血压的发展和维持有关的变化。这项研究将描述FG调节的ET-1产生的机制，以及由此产生的增加的血管收缩，加剧高血压期间的微循环并发症。