Dual role of VEGF-induced heme-oxygenase-1 in angiogenesis.
Heme-oxygenase-1 (HO-1) is an inducible cytoprotective molecule that displays antioxidant, antiapoptotic, and antiinflammatory effects. In addition, HO-1 appears to have a complex role in angiogenesis. Recent in vivo studies report that vascular endothelial growth factor (VEGF) regulates HO-1 expression and activity in vascular endothelial cells (ECs) and that inhibition of HO-1 abrogates VEGF-induced endothelial activation and subsequent angiogenesis, while promoting VEGF-induced monocyte recruitment and inflammatory angiogenesis. HO-1 may also regulate the synthesis and activity of VEGF, resulting in a positive-feedback loop. In contrast, HO-1 activity has the opposite effect on lipopolysaccharide-driven inflammatory angiogenesis, inhibiting leukocyte invasion and preventing subsequent angiogenesis. In this review, we summarize the current understanding of the role of HO-1 in angiogenesis. We conclude that further investigation, using targeted molecular approaches specifically to alter HO-1 activity, are required to develop our understanding of the role of HO-1 and its products, carbon monoxide, biliverdin, bilirubin, and free iron in angiogenesis. We propose that during chronic inflammation, HO-1 has two roles, first an antiinflammatory action inhibiting leukocyte infiltration, and second, promotion of VEGF-driven noninflammatory angiogenesis, which facilitates tissue repair. Additional studies will help determine whether modulating the activity of HO-1 and/or its products has therapeutic potential in chronic inflammatory dise.
Bussolati
Benedetta
B
Department of Biology and Clinical Science, University of Torino, Ospedale S. Giovanni Battista, Italy.
Mason
Justin C
JC
D000818:Animals; D005544:Forecasting; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology* / Q000502:physiology
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1