Published online before print January 6, 2005, doi: 10.1161/01.RES.0000155330.07887.EE
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© 2005 American Heart Association, Inc.
Molecular Medicine |
Hepatocyte Growth Factor Suppresses Vascular Endothelial Growth Factor-Induced Expression of Endothelial ICAM-1 and VCAM-1 by Inhibiting the Nuclear Factor-
B Pathway
From the Department of Biochemistry (J.-K.M., Y.-G.K.), College of Sciences, Yonsei University, Seoul; the Department of Biochemistry (J.-K.M., S.W.K.), College of Natural Sciences, Department of Molecular and Cellular Biochemistry (Y.-M.K.), School of Medicine, Kangwon National University, Chunchon, Kangwon-Do; the Division of Molecular Life Science (Y.-M.L., G.T.O.) and Center for Cell Signaling Research (S.-Y.L.), Ewha Womans University, Seoul; the Division of Molecular and Life Science (Y.S.G.), Pohang University of Science and Technology, Pohang, Kyungbuk; and the Department of Ophthalmology, Seoul National University College of Medicine and Seoul Artificial Eye Center, Clinical Research Institute (J.H.K.), Seoul National University Hospital, Republic of Korea.
Correspondence to Young-Guen Kwon, PhD, Department of Biochemistry, College of Sciences, Yonsei University, Seoul, 120-749, Republic of Korea. E-mail ygkwon{at}yonsei.ac.kr
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 I
B kinase activity, and this in turn prevented the activation of the inflammatory transcription factor NF-B. Taken together, our results demonstrate that HGF suppresses VEGF-induced inflammation presumably by inhibiting the endothelial NF-B 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.
Key Words: therapeutic angiogenesis • inflammation • cell adhesion molecule • IB kinase
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