title: Hepatocyte growth factor suppresses vascular endothelial growth factor-induced expression of endothelial ICAM-1 and VCAM-1 by inhibiting the nuclear factor-kappaB pathway.
abstract: Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are potent angiogenic factors that have been used clinically to induce angiogenesis. However, concerns have been raised about VEGF because of its proinflammatory actions, which include enhancing the adhesion of leukocytes to endothelial cells. We have examined the possible antiinflammatory effects of HGF on the vasculature. HGF, unlike VEGF, did not alter leukocyte adhesion to endothelial cells. Instead it inhibited VEGF-induced leukocyte-endothelial cell interactions and the endothelial expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). In a skin inflammation model, VEGF-treated mice showed a significant increase of leukocytes infiltrated or adherent to the luminal surface of blood vessels, as compared with vehicle- or HGF-treated mice. The VEGF effect was markedly suppressed by coadministration of HGF. RT-PCR and promoter analysis revealed that HGF downregulated VEGF-mediated expression of ICAM-1 and VCAM-1 at the transcriptional level. Furthermore, these inhibitory effects coincided with suppression of IkappaB kinase activity, and this in turn prevented the activation of the inflammatory transcription factor NF-kappaB. Taken together, our results demonstrate that HGF suppresses VEGF-induced inflammation presumably by inhibiting the endothelial NF-kappaB pathway. This suggests that combined treatment with HGF and VEGF could be superior to treatment with either factor alone for enhancing therapeutic angiogenesis while avoiding inflammation.
authors.affiliation: Department of Biochemistry, College of Sciences, Yonsei University, Seoul, Republic of Korea.
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Min
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Lee
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Yong Song
authors.initials: YS
authors.lastname: Gho
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002460:Cell Line; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000502:physiology; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D020298:U937 Cells / Q000737:chemistry / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: D015815:Cell Adhesion Molecules; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D042442:Vascular Endothelial Growth Factors; D018799:Intercellular Adhesion Molecule-1; D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse