The protean manifestations of portal hypertension (PHT) leads to the death of over 100,000 Americans annually, and disproportionately targets minorities and women due to their greater susceptibility to liver disease. Hermorrhagic shock is the most common and lethal complication of portal hypertension where patients tolerate massive hemorrhage poorly, developing renal failure and adult respiratory distress syndrome. Current treatments and modalities may actually aggravate the underlying cause of the bleeding. Following the initial obstruction to portal blood flow, an elevation in portal pressure is maintained due to a marked splanchnic and systemic arterial hyperemia (~hyperdynamic circulation~). During hemorrhage and volume resuscitation, ortal pressure actually rises to levels higher than baseline, recreating the risk factors for continued bleeding. This proposal seeks to determine the relationship between mechanical forces, the putative mediators of splanchnic blood flow (NO, PGI2, angiotensiin II and endothelin) and the abnormal vasular response to hemorrhage in PHT. Our central hypothesis is that changes in intraluminal mechanical forces (shear stress and intraluminal pressure) increase the expression and/or activity of vasodilator substances which chronically regulate pressor hormone receptor transmembrane signaling in PHT that ultimately determines the responsiveness of the hyperemic vasculature to hemorrhagic shock and resuscitation. Specifically, we hypothesize that mechanical forces induce specific physiological and anatomical alterations in the PHT vessel including the expression and function of endothelial inhibitory guanine nucleotide regulatory proteins (Gialpha) that the control the production of NO and PGI2 from the vascular endothelium. we further hypothesize that the altered vascular response to endogenous vasoconstrictor stimuli (antiogensin II, endothelin) in PHT at baseline and following hemorrhagic shock is due to chronic regulation or pressor hormone receptor transmembrane signaling by increased vasodilator production. Using both in vivo models of PHT, with or without cirrhosis (partial portal vein ligated (PVL) and bile duct-ligated (BDL) following hemmorrhagic shock and resuscitation, in conjunction with an in vitro perfused transcapillary endothelial and vascular smooth muscle co-culture system (which mimics the in vivo architecture and flow/pressure parameters), we will determine the role of mechanical forces, vasoactrive substances, and hepatic parenchymal dysfunction on vascular signal mechanisms that contribute to and/or maintain the vasculopathy of PHT. These experiments will provide information central to our understanding of PHT and hemorrhagic shock, and should further lead directly to the development of effective treatment programs.
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