TY - JOUR
T1 - Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver
AU - Jagavelu, Kumaravelu
AU - Routray, Chittaranjan
AU - Shergill, Uday
AU - O'Hara, Steven P.
AU - Faubion, William
AU - Shah, Vijay H.
PY - 2010/8
Y1 - 2010/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77955686233&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955686233&partnerID=8YFLogxK
U2 - 10.1002/hep.23739
DO - 10.1002/hep.23739
M3 - Article
C2 - 20564354
AN - SCOPUS:77955686233
SN - 0270-9139
VL - 52
SP - 590
EP - 601
JO - Hepatology
JF - Hepatology
IS - 2
ER -