Nitric oxide (NO) plays an important role in the regulation of hepatic vasodilator tone. Intrahepatic vasoconstriction contributes to the development of an increase in portal pressure in hepatic cirrhosis. The source of this vasoconstriction appears to be an alteration in the sinusoidal endothelial cell (SEC), a unique microvascular cell which lines the resistance vessels in the hepatic sinusoids and expresses NO synthase (NOS) III. Shear stress is a physiologic biomechanical force which has been found to modulate regional blood flow through the regulation of endothelial cell production of vasodilator substances such as NO. Preliminary studies suggest that shear stress activates a tyrosine phosphorylation cascade and additionally causes a subcellular redistribution of NO synthase (NOS) III, two events which are novel mechanisms of regulation of NOS III. The long term objective of these studies is to elucidate the mechanisms of regulation of NO production in the hepatic microcirculation by shear stress and to examine how they may contribute to the hemodynamic alterations seen in cirrhosis. Understanding the mechanisms that regulate portal pressure is vital as the development of portal hypertension is the single most important factor that determines which patients with cirrhosis will develop complications. Defining the mechanisms that regulate nitric oxide production in SEC may lead to therapeutic options whereby NO activity may be pharmacologically or genetically modulated and benefit patients with cirrhosis and portal hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08DK002529-02
Application #
2878894
Study Section
Special Emphasis Panel (SRC)
Program Officer
Podskalny, Judith M,
Project Start
1998-09-30
Project End
2003-06-30
Budget Start
1998-09-30
Budget End
1999-06-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Cao, Sheng; Yao, Janet; Shah, Vijay (2003) The proline-rich domain of dynamin-2 is responsible for dynamin-dependent in vitro potentiation of endothelial nitric-oxide synthase activity via selective effects on reductase domain function. J Biol Chem 278:5894-901
Hendrickson, H; Chatterjee, S; Cao, S et al. (2003) Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver. Am J Physiol Gastrointest Liver Physiol 285:G652-60
Cao, S; Yao, J; McCabe, T J et al. (2001) Direct interaction between endothelial nitric-oxide synthase and dynamin-2. Implications for nitric-oxide synthase function. J Biol Chem 276:14249-56
Shah, V; Cao, S; Hendrickson, H et al. (2001) Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats. Am J Physiol Gastrointest Liver Physiol 280:G1209-16
Shah, V; Chen, A F; Cao, S et al. (2000) Gene transfer of recombinant endothelial nitric oxide synthase to liver in vivo and in vitro. Am J Physiol Gastrointest Liver Physiol 279:G1023-30
Shah, V; Wiest, R; Garcia-Cardena, G et al. (1999) Hsp90 regulation of endothelial nitric oxide synthase contributes to vascular control in portal hypertension. Am J Physiol 277:G463-8
Shah, V; Toruner, M; Haddad, F et al. (1999) Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology 117:1222-8