Vascular Response to Hemmorhage in Portal Hyprtension

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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.