Altered hepatic vascular regulation is a common event following shock or sepsis. Recent work shows that this is related to increased constrictor response to endothelin that is associated with decreased eNOS activation. We now hypothesize that inflammatory and oxidative stress associated with shock and sepsis disrupt signaling of endothelin-1 via effects on proteins sequestered in caveolae. The result is uncoupling of ET receptors from eNOS activation, but not from constrictor signaling. Ultimately vascular dysregulation potentiates liver injury and inflammatory response. Given the many signaling molecules that are sequestered in the caveolae, the potential significance of this investigation goes beyond vascular regulation and may provide valuable insights regarding cell signaling in general during shock and sepsis. In order to test this hypothesis, we propose the following aims.
Aim 1 : Test whether alterations in proteins associated with caveolae is a common pathway in shock related injuries.
Aim 2 : Test whether changes in basal expression of caveolae-associated proteins result in altered endothelin-1 signaling.
Aim 3 : Test whether stress-induced changes can be mimicked by manipulation of components of the caveolar domains.
Aim 4 : Test whether manipulation of mechanisms identified as important in aims 1-3 have a significant impact on vascular regulation, distribution of tissue oxygen and liver injury in vivo. Upon completion of the above aims, we will have elucidated the effect of prototypical in vitro stresses as well as clinically relevant in vivo stresses on regulation of proteins associated with caveolar domains that affect the interaction between endothelin and NO. We will also have determined the functional significance of these changes for endothelin signaling in vitro and for hepatic vascular regulation in vivo. The hepatic microcirculation has many unique aspects; however, there is evidence that these mechanisms with some modifications may be virtually ubiquitous in vascular cells. Thus our findings are likely to have much broader application than just understanding of liver injury during shock states.
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