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.
|Liu, Jingjing; Zhao, Jiawei; Lee, Jen-Fu et al. (2013) 3-amino-4-(3-hexylphenylamino)-4-oxobutyl phosphonic acid (W146), a Selective Antagonist of Sphingosine-1-phospahte Receptor Subtype 1, Enhances AMD3100-stimulated Mobilization of Hematopoietic Stem Progenitor Cells in Animals. J Biochem Pharmacol Res 1:197-203|
|Lominadze, David; Tyagi, Neetu; Sen, Utpal et al. (2012) Homocysteine alters cerebral microvascular integrity and causes remodeling by antagonizing GABA-A receptor. Mol Cell Biochem 371:89-96|
|Qipshidze, Natia; Tyagi, Neetu; Metreveli, Naira et al. (2012) Autophagy mechanism of right ventricular remodeling in murine model of pulmonary artery constriction. Am J Physiol Heart Circ Physiol 302:H688-96|
|Muradashvili, Nino; Qipshidze, Natia; Munjal, Charu et al. (2012) Fibrinogen-induced increased pial venular permeability in mice. J Cereb Blood Flow Metab 32:150-63|
|Munjal, Charu; Tyagi, Neetu; Lominadze, David et al. (2012) Matrix metalloproteinase-9 in homocysteine-induced intestinal microvascular endothelial paracellular and transcellular permeability. J Cell Biochem 113:1159-69|
|Muradashvili, Nino; Tyagi, Reeta; Lominadze, David (2012) A dual-tracer method for differentiating transendothelial transport from paracellular leakage in vivo and in vitro. Front Physiol 3:166|
|Qipshidze, Natia; Metreveli, Naira; Mishra, Paras K et al. (2012) Hydrogen sulfide mitigates cardiac remodeling during myocardial infarction via improvement of angiogenesis. Int J Biol Sci 8:430-41|
|Qipshidze, Natia; Metreveli, Naira; Lominadze, David et al. (2011) Folic acid improves acetylcholine-induced vasoconstriction of coronary vessels isolated from hyperhomocysteinemic mice: an implication to coronary vasospasm. J Cell Physiol 226:2712-20|
|Muradashvili, Nino; Tyagi, Neetu; Tyagi, Reeta et al. (2011) Fibrinogen alters mouse brain endothelial cell layer integrity affecting vascular endothelial cadherin. Biochem Biophys Res Commun 413:509-14|
|Qipshidze, Natia; Tyagi, Neetu; Sen, Utpal et al. (2010) Folic acid mitigated cardiac dysfunction by normalizing the levels of tissue inhibitor of metalloproteinase and homocysteine-metabolizing enzymes postmyocardial infarction in mice. Am J Physiol Heart Circ Physiol 299:H1484-93|
Showing the most recent 10 out of 28 publications