Angiogenesis-independent endothelial protection of liver: role of VEGFR-1.
The vascular endothelium was once thought to function primarily in nutrient and oxygen delivery, but recent evidence suggests that it may play a broader role in tissue homeostasis. To explore the role of sinusoidal endothelial cells (LSECs) in the adult liver, we studied the effects of vascular endothelial growth factor (VEGF) receptor activation on mouse hepatocyte growth. Delivery of VEGF-A increased liver mass in mice but did not stimulate growth of hepatocytes in vitro, unless LSECs were also present in the culture. Hepatocyte growth factor (HGF) was identified as one of the LSEC-derived paracrine mediators promoting hepatocyte growth. Selective activation of VEGF receptor-1 (VEGFR-1) stimulated hepatocyte but not endothelial proliferation in vivo and reduced liver damage in mice exposed to a hepatotoxin. Thus, VEGFR-1 agonists may have therapeutic potential for preservation of organ function in certain liver disorders.
LeCouter
Jennifer
J
Departments of Molecular Oncology, Protein Engineering, and Pathology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Moritz
Dirk R
DR
Li
Bing
B
Phillips
Gail Lewis
GL
Liang
Xiao Huan
XH
Gerber
Hans-Peter
HP
Hillan
Kenneth J
KJ
Ferrara
Napoleone
N
D000818:Animals; D016466:CHO Cells; D002251:Carbon Tetrachloride / Q000633:toxicity; D002455:Cell Division; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D018920:Coculture Techniques; D006224:Cricetinae; D004261:DNA Replication; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000098:blood supply / Q000166:cytology* / Q000473:pathology / Q000502:physiology*; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008115:Liver Regeneration; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009154:Mutation; D009336:Necrosis; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017228:Hepatocyte Growth Factor; D002251:Carbon Tetrachloride; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2