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: 7788167
• 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/7788167
• 关键词: Acetates; Age; Animals; Attenuated; Big Endothelin; Binding; Blood; Blood Pressure; Cardiovascular system; Cerebrovascular Disorders; Confocal Microscopy; Control Animal; Deoxycorticosterone; Development; Dose; 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; Integrin alpha5beta1; Integrins; Intercellular adhesion molecule 1; JUN gene; MALDI-TOF Mass Spectrometry; Maintenance; Mediating; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Operative Surgical Procedures; 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; Weibel-Palade Bodies; animal data; arteriole; base; high risk; inflammatory marker; inhibitor/antagonist; non-genetic; novel; programs; receptor; research study; response; 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)：高血压伴随着血浆纤维蛋白原(Fg)含量的增加。我们报道了FG与动脉壁结合引起血管收缩，这种收缩是由细胞间黏附分子-1(ICAM-1)介导的。此外，阻断内皮素A型受体可减弱FG引起的血管收缩。在我们的初步研究中，FG与内皮细胞的结合促进了内皮素-1(ET-1)的产生。此外，FG与内皮细胞(ECs)结合可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α5beta1整合素的激活导致ERK和c-Jun-NH2末端激酶(JNK)的磷酸化。纤维蛋白原诱导的血管收缩在高血压时增强，调节ET-1的产生是由于Webel-Palade小体(WPB)的胞吐。我们推测，在高血压期间，FG与内皮细胞ICAM-1(可能还有α5beta1)的结合增加，通过ERK(可能还有JNK)信号诱导WPB胞吐增加，导致ET-1的产生增加，从而增强血管收缩。根据我们的发现，FG与内皮细胞的结合改变了EC蛋白质组，这可能与WPB的胞吐作用有关，我们将确定这些FG诱导的细胞变化是否与ET-1的释放有关，从而与血管收缩有关。本研究的具体目的是：1)评估FG与ICAM-1的结合、ET-1的合成以及高血压时的血管收缩；2)确定FG诱导的ET-1产生和高血压时血管收缩增强的信号通路(ERK和/或JNK参与)；3)确定FG结合改变的EC蛋白在FG诱导的WPB在高血压时排出中的功能作用。高血压诱导的增强的FG与内皮ICAM-1(和α5beta1)的结合，ERK(和JNK)信号转导的作用，以及FG与ECs结合改变的蛋白质在WPbs的排泄增加和ET-1的产生中的作用，从而导致血管收缩增强，将被确定。遗传性(SHR)和非遗传性(DOCA-SALT)大鼠高血压模型将在高血压的早期和已建立的阶段进行研究，以确定与高血压的发展和维持相关的变化。这项研究将描述FG调节产生ET-1的机制，以及由此导致的血管收缩增加，从而加剧高血压期间的微循环并发症。