Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: induction of angiogenesis and inhibition of leukocytic infiltration

Heme-oxygenases (HOs) catalyze 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...

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Published in:	Blood 2004-02, Vol.103 (3), p.761-766
Main Authors:	Bussolati, Benedetta, Ahmed, Asif, Pemberton, Helen, Landis, R. Clive, Di Carlo, Francesco, Haskard, Dorian O., Mason, Justin C.
Format:	Article
Language:	eng
Subjects:	Animals Biological and medical sciences Cell Line Cell Movement - drug effects Cells, Cultured Enzyme Induction - drug effects Fibroblast Growth Factor 1 - pharmacology Fundamental and applied biological sciences. Psychology Heme Oxygenase (Decyclizing) - biosynthesis Heme Oxygenase-1 Humans Inflammation Inflammation - pathology Inflammation - physiopathology Leukocytes - cytology Leukocytes - drug effects Membrane Proteins Mice Models, Biological Molecular and cellular biology Neovascularization, Physiologic - drug effects Recombinant Proteins - pharmacology Vascular Endothelial Growth Factor A - pharmacology Vascular Endothelial Growth Factor A - physiology
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Summary:	Heme-oxygenases (HOs) catalyze 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. Vascular endothelial growth factor (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) a lipopolysaccharide (LPS)–induced model of inflammatory angiogenesis in which angiogenesis is secondary to leukocyte invasion. Pharmacologic inhibition of HO-1 induced marked leukocytic infiltration that enhanced VEGF-induced angiogenesis. However, in the presence of an anti-CD18 monoclonal antibody (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 2 roles: first, an anti-inflammatory action inhibiting leukocyte infiltration; and second, promotion of VEGF-driven noninflammatory angiogenesis that facilitates tissue repair.
ISSN:	0006-4971 1528-0020