Capillarization is the loss of the highly differentiated sinusoidal endothelial cell (SEC) phenotype with loss of fenestration, thickening of the SEC, and formation of an organized basement membrane. Studies to-date suggest that capillarization is permissive for fibrosis and that understanding capillarization may therefore be crucial for understanding the development of fibrosis. The objective of the current proposal is to further delineate normal regulation of the sinusoidal endothelial cell phenotype and then determine the changes in these regulatory pathways that lead to capillarization. Two of the changes that lead to capillarization are decreased protein expression of vascular endothelial growth factor (VEGF) and VEGF receptors 1 and 2.
Specific Aim I examines whether the decreased protein expression of VEGF and VEGF receptors is due to decreased gene expression and, if so, whether exogenous hepatocyte growth factor (HGF) normalizes VEGF and VEGF receptor expression in capillarization.
Specific Aim II examines whether there is decreased activation of HGF in capillarization, examines the pathways of HGF activation and how the activation pathways are altered in capillarization.
Specific Aim III will attempt to develop a workable model of reversal of capillarization and examines the changes that occur during reversal of capillarization.
Specific Aim I V examines how nitric oxide maintains SEC phenotype.

Public Health Relevance

The final common pathway leading to morbidity and mortality from most liver diseases is the development of fibrosis, cirrhosis and its complications, and then either liver failure or liver cancer. This project examines the mechanisms that lead to capillarization, a change within the liver microcirculation that is permissive for fibrosis. Improved understanding of this largely unexplored area may lead to strategies to prevent fibrosis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
DeLeve, Laurie D (2015) Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 61:1740-6
Xie, Guanhua; Wang, Xiangdong; Wang, Lei et al. (2012) Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 142:918-927.e6
Warren, Alessandra; Cogger, Victoria C; Fraser, Robin et al. (2011) The effects of old age on hepatic stellate cells. Curr Gerontol Geriatr Res 2011:439835
Cogger, Victoria C; McNerney, Gregory P; Nyunt, Tun et al. (2010) Three-dimensional structured illumination microscopy of liver sinusoidal endothelial cell fenestrations. J Struct Biol 171:382-8
Xie, Guanhua; Wang, Lin; Wang, Xiangdong et al. (2010) Isolation of periportal, midlobular, and centrilobular rat liver sinusoidal endothelial cells enables study of zonated drug toxicity. Am J Physiol Gastrointest Liver Physiol 299:G1204-10
Deleve, Laurie D; Wang, Xiangdong; Guo, Yumei (2008) Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 48:920-30
DeLeve, Laurie D; Wang, Xiangdong; Kanel, Gary C et al. (2008) Prevention of hepatic fibrosis in a murine model of metabolic syndrome with nonalcoholic steatohepatitis. Am J Pathol 173:993-1001
DeLeve, Laurie D; Wang, Xiangdong; McCuskey, Margaret K et al. (2006) Rat liver endothelial cells isolated by anti-CD31 immunomagnetic separation lack fenestrae and sieve plates. Am J Physiol Gastrointest Liver Physiol 291:G1187-9
DeLeve, Laurie D; Wang, Xiangdong; Hu, Liping et al. (2004) Rat liver sinusoidal endothelial cell phenotype is maintained by paracrine and autocrine regulation. Am J Physiol Gastrointest Liver Physiol 287:G757-63