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Blood, 1 February 2004, Vol. 103, No. 3, pp. 761-766. Prepublished online as a Blood First Edition Paper on October 2, 2003; DOI 10.1182/blood-2003-06-1974. This Article Full Text (PDF) All Versions of this Article: 2003-06-1974v1 103/3/761    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bussolati, B. Articles by Mason, J. C Search for Related Content PubMed PubMed Citation Articles by Bussolati, B. Articles by Mason, J. C Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted June 18, 2003 Accepted September 22, 2003 Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: induction of angiogenesis and inhibition of leukocytic infiltration Benedetta Bussolati, Asif Ahmed*, Helen Pemberton, Robert Clive Landis, Francesco Di Carlo, Dorian O Haskard, and Justin C Mason Department of Biology and Clinical Science, University of Torino, Turin, Italy Department of Reproductive and Vascular Biology, University of Birmingham, Birmingham, United Kingdom Cardiovascular Medicine Unit, The Eric Bywaters Center, Imperial College London, London, United Kingdom * Corresponding author; email: a.s.ahmed{at}bham.ac.uk. Heme-oxygenases (HO) catalyse the conversion of heme into carbon monoxide and biliverdin. HO-1 is induced during hypoxia, ischemia/reperfusion and inflammation, providing cytoprotection and inhibiting leukocyte migration to inflammatory sites. Although in vitro studies have suggested an additional role for HO-1 in angiogenesis, the relevance of this in vivo remains unknown. We investigated the involvement of HO-1 in angiogenesis in vitro and in vivo. VEGF induced prolonged HO-1 expression and activity in human endothelial cells and HO-1 inhibition abrogated VEGF-driven angiogenesis. Two murine models of angiogenesis were used: (1) angiogenesis initiated by addition of VEGF to Matrigel and (2) an LPS-induced model of inflammatory angiogenesis in which angiogenesis is secondary to leukocyte invasion. Pharmacological inhibition of HO-1 induced marked leukocytic infiltration which enhanced VEGF-induced angiogenesis. However, in the presence of an anti-CD18 mAb to block leukocyte migration, VEGF-induced angiogenesis was significantly inhibited by HO-1 antagonists. Furthermore, in the LPS-induced model of inflammatory angiogenesis, induction of HO-1 with cobalt protoporphyrin significantly inhibited leukocyte invasion into LPS-conditioned Matrigel and thus prevented the subsequent angiogenesis. We therefore propose that during chronic inflammation HO-1 has two roles, first an anti-inflammatory action inhibiting leukocyte infiltration and second promotion of VEGF-driven non-inflammatory angiogenesis which facilitates tissue repair. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: VEGF: is it just an inducer of heme oxygenase-1 expression? Miguel P. Soares Blood 2004 103: 751. [Full Text] [PDF] This article has been cited by other articles: L. Bellner, L. Martinelli, A. Halilovic, K. Patil, N. Puri, M. W. Dunn, R. F. Regan, and M. L. Schwartzman Heme Oxygenase-2 Deletion Causes Endothelial Cell Activation Marked by Oxidative Stress, Inflammation, and Angiogenesis J. Pharmacol. 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