These authors contributed equally to this work.
Liver Failure/Cirrhosis/Portal Hypertension
Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver†
Article first published online: 28 APR 2010
Copyright © 2010 American Association for the Study of Liver Diseases
Volume 52, Issue 2, pages 590–601, August 2010
How to Cite
Jagavelu, K., Routray, C., Shergill, U., O'Hara, S. P., Faubion, W. and Shah, V. H. (2010), Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver. Hepatology, 52: 590–601. doi: 10.1002/hep.23739
Potential conflict of interest: Nothing to report.
- Issue published online: 23 JUL 2010
- Article first published online: 28 APR 2010
- Manuscript Accepted: 22 APR 2010
- Manuscript Received: 18 JAN 2010
- National Institutes of Health [grants]. Grant Numbers: R01 DK 59615, R01 HL 86990
- (Clinical Core). Grant Number: P30 DK 084567
Angiogenesis defines the growth of new blood vessels from preexisting vascular endothelial networks and corresponds to the wound healing process that is typified by the process of liver fibrosis. Liver fibrosis is also associated with increased endotoxin within the gut lumen and its associated portal circulation. However, the interrelationship of gut endotoxin and its receptor, toll-like receptor 4 (TLR4), with liver fibrosis and associated angiogenesis remains incompletely defined. Here, using complementary genetic, molecular, and pharmacological approaches, we provide evidence that the pattern recognition receptor that recognizes endotoxin, TLR4, which is expressed on liver endothelial cells (LECs), regulates angiogenic responses both in vitro and in vivo. Mechanistic studies have revealed a key role for a cognate TLR4 effector protein, myeloid differentiation protein 88 (MyD88), in this process, which culminates in extracellular protease production that regulates the invasive capacity of LECs, a key step in angiogenesis. Furthermore, TLR4-dependent angiogenesis in vivo corresponds to fibrosis in complementary liver models of fibrosis. Conclusion: These studies provide evidence that the TLR4 pathway in LECs regulates angiogenesis through its MyD88 effector protein by regulating extracellular protease production and that this process is linked to the development of liver fibrosis. (HEPATOLOGY 2010;)