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

Bussolati, Benedetta, Ahmed, Asif, Pemberton, Helen, Landis, R. Clive, di Carlo, Francesco, Haskard, Dorian O. and Mason, Justin C. (2004). Bifunctional role for VEGF-induced heme oxygenase-1 in vivo:induction of angiogenesis and inhibition of leukocytic infiltration. Blood, 103 (3), pp. 761-766.


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.

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Divisions: Life & Health Sciences
Life & Health Sciences > Biosciences
Aston Medical School
Full Text Link: http://bloodjou ... ntent/103/3/761
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Published Date: 2004-02
Authors: Bussolati, Benedetta
Ahmed, Asif
Pemberton, Helen
Landis, R. Clive
di Carlo, Francesco
Haskard, Dorian O.
Mason, Justin C.

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