title: Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: GI Research Unit and Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Kumaravelu
authors.initials: K
authors.lastname: Jagavelu
authors.forename: Chittaranjan
authors.initials: C
authors.lastname: Routray
authors.forename: Uday
authors.initials: U
authors.lastname: Shergill
authors.forename: Steven P
authors.initials: SP
authors.lastname: O'Hara
authors.forename: William
authors.initials: W
authors.lastname: Faubion
authors.forename: Vijay H
authors.initials: VH
authors.lastname: Shah
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D009389:Neovascularization, Pathologic; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D051197:Toll-Like Receptor 4