Vascular Response to Hemmorhage in Portal Hyprtension

Summary

Principal Investigator: SHUNICHIRO OKADA
Abstract: 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.
Funding Period: 1993-09-01 - 2007-11-30
more information: NIH RePORT

Top Publications

  1. pmc Ethanol inhibits monocyte chemotactic protein-1 expression in interleukin-1{beta}-activated human endothelial cells
    John P Cullen
    Department of Surgery, University of Rochester Medical Center, Rochester, New York 14642, USA
    Am J Physiol Heart Circ Physiol 289:H1669-75. 2005
  2. ncbi Ethanol inhibits pulse pressure-induced vascular smooth muscle cell migration by differentially modulating plasminogen activator inhibitor type 1, matrix metalloproteinase-2 and -9
    John P Cullen
    Department of Surgery, University of Rochester Medical Center, Rochester, NewYork 14642 8410, USA
    Thromb Haemost 94:639-45. 2005
  3. pmc Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension
    N J Skill
    Dept of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Am J Physiol Gastrointest Liver Physiol 295:G953-64. 2008

Scientific Experts

  • N J Skill
  • John P Cullen
  • Paul A Cahill
  • Shariq Sayeed
  • James V Sitzmann
  • Eileen M Redmond
  • Nicholas G Theodorakis
  • Ying Jin
  • Youngrin Kim

Detail Information

Publications3

  1. pmc Ethanol inhibits monocyte chemotactic protein-1 expression in interleukin-1{beta}-activated human endothelial cells
    John P Cullen
    Department of Surgery, University of Rochester Medical Center, Rochester, New York 14642, USA
    Am J Physiol Heart Circ Physiol 289:H1669-75. 2005
    ..These actions of EtOH may underlie, in part, its cardiovascular protective effects in vivo...
  2. ncbi Ethanol inhibits pulse pressure-induced vascular smooth muscle cell migration by differentially modulating plasminogen activator inhibitor type 1, matrix metalloproteinase-2 and -9
    John P Cullen
    Department of Surgery, University of Rochester Medical Center, Rochester, NewYork 14642 8410, USA
    Thromb Haemost 94:639-45. 2005
    ..These data provide a molecular mechanism mediating the inhibitory effect of ethanol on pulse-pressure-induced SMC migration and may be relevant to the cardioprotective effects of ethanol in vivo...
  3. pmc Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension
    N J Skill
    Dept of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Am J Physiol Gastrointest Liver Physiol 295:G953-64. 2008
    ..Identification of additional target sites downstream of COX may benefit the >27,000 patients whom die annually from cirrhosis in the United States alone...