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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1537.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Heme Oxygenase-1 Increases Endothelial Progenitor Cells

Ben J. Wu; Robyn G. Midwinter; Carlos Cassano; Konstanze Beck; Yutang Wang; Dechaboon Changsiri; Jennifer R. Gamble; Roland Stocker

From the Centre for Vascular Research, Bosch Institute and Discipline of Pathology, School of Medical Sciences, Faculty of Medicine (B.J.W., R.G.M., K.B., Y.W., D.C., R.S.), and the Centenary Institute of Cancer Medicine and Cell Biology (C.C., J.R.G.), University of Sydney, Australia. Current affiliation for B.J.W.: the Heart Research Institute, Newtown NSW, Australia.

Correspondence to Prof Roland Stocker, Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, Faculty of Medicine, University of Sydney, Medical Foundation Building K25, 92-94 Parramatta Road, NSW 2006, Australia. E-mail rstocker{at}med.usyd.edu.au

Objectives— Induction of heme oxygenase-1 (HO-1) protects against atherosclerotic disease in part by promoting reendothelialization. As endothelial progenitor cells (EPCs) contribute to reendothelialization, we examined the role of HO-1 on bone marrow and circulating EPCs.

Methods and Results— In a rabbit model of aortic balloon injury, pharmacological induction of HO-1 enhanced reendothelialization at sites with and without adjacent blood vessels, the latter indicative of a contribution by EPCs. Coinciding with maximal HO-1 induction in the injured vessel, plasma concentrations of bilirubin and the numbers of circulating progenitor cells were elevated. Both processes were abolished by cotreatment of the animals with an inhibitor of HO-1. Inducers of HO-1 promoted bone marrow cells to form progenitor cell colonies, and Flk1⁺/Sca-1⁺-cells to adhere to the luminal surface of the injured vessel. In noninjured mice, HO-1 inducers also increased bone marrow and circulating EPCs, and the ability of these cells to differentiate and form colonies. Compared to wild-type mice, bone marrow cells from HO-1^–/– mice generated fewer endothelial colony-forming cells, and HO-1 inducers failed to promote CFU-Hill colony formation.

Conclusions— These findings suggest that HO-1 contributes to vascular repair by increasing circulating EPCs derived from the bone marrow.

This study examined the effect of heme oxygenase-1 (HO-1) on circulating endothelial progenitor cells (EPCs) in the context of reendothelialization after vascular injury. HO-1 increased the numbers of circulating and bone marrow EPCs and their ability to mature and form colonies. These novel activities likely contribute to the ability of HO-1 to promote reendothelialization.

Key Words: bilirubin • carbon monoxide • endothelial cells • succinobucol • vascular injury