After vascular injury, heme oxygenase-1/carbon monoxide enhances re-endothelialization via promoting mobilization of circulating endothelial progenitor cells.

Abstract

Heme oxygenase-1 (HO-1), a heme degradation enzyme with multiple vasoprotective functions, is systemically induced in pathophysiological states associated with oxidative stress. To evaluate the impact of systemic HO-1 expression on circulating endothelial progenitor cells (EPCs) and re-endothelialization after vascular injury in an animal model. Mice received an intravenous (i.v.) injection of the adenovirus-bearing HO-1 gene (Adv-HO-1). The serum levels of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) were determined by ELISA and gene expression examined by quantitative real-time PCR. Circulating EPCs were characterized by flow cytometry and in vitro culture. EPC recruitment and re-endothelialization in injured arteries were assessed in mice receiving GFP+-bone marrow transplantation and guide wire-induced carotid injury. The effect of carbon monoxide (CO), a byproduct from heme degradation by HO-1, was assessed by exposing mice to 250 p.p.m. CO for 2 h day(-1). Systemic HO-1 induction led to elevated serum levels of VEGF and SDF-1 and an increase in circulating EPCs. The re-endothelialization of denuded vessels was accelerated in mice with systemic HO-1 overexpression. A further experiment demonstrated that both EPC mobilization and re-endothelialization were significantly attenuated in mice with HO-1 deficiency. The increase in EPC mobilization and enhanced re-endothelialization was also observed in mice exposed to CO prior to carotid injury. The CO-mediated effect was associated with an increase in circulating SDF-1 but not VEGF. These findings support a vital role of HO-1 and its reaction byproduct, CO, in vascular repair through enhancing EPC mobilization.