Heme oxygenase-1 and carbon monoxide in vascular pathobiology: focus on angiogenesis

Abstract

Angiogenesis involves the formation of new blood vessels and is critical for fundamental events such as development and repair after injury. Perturbances in angiogenesis contribute to the pathogenesis of diverse clinical conditions including cancer, complications of diabetes mellitus, ischemia/reperfusion injury of the heart and other organs, and preeclampsia, as well as a number of inflammatory disorders. Recent work has identified heme oxygenase-1 and its gaseous product, carbon monoxide, to possess potent proangiogenic properties in addition to well-recognized antiinflammatory, antioxidant, and antiapoptotic effects. Angiogenic factors, such as vascular endothelial growth factor and stromal cell-derived factor-1, mediate their proangiogenic effects through induction of heme oxygenase-1, making it an attractive target for therapeutic intervention. This review will provide an overview of the role of heme oxygenase-1 and carbon monoxide in angiogenesis.

Conflict of interest statement

Disclosures

None.

Figures

Figure 1

HO enzymatic reaction. Heme (iron protoporphyrin IX) released from heme proteins is cleaved by HO to yield equimolar quantities of iron, CO, and biliverdin. Biliverdin is then converted to bilirubin by biliverdin reductase.

Figure 2

Induction of VEGF synthesis and HO-1. Several mediators known to enhance VEGF expression exert their effects through HO-1. For hypoxia, the involvement of HO-1 can be cell-type dependent. LPS indicates lipopolysaccharide.

Figure 3

Redistribution of VASP to filopodia in response to a CO donor. Human EPC isolated from peripheral blood were treated with vehicle (left) or tricarbonyl-dichlororuthenium (II) dimer (CORM-2, CO donor) (10 μmol/L) (right) for 15 minutes before fixation and immunocytochemistry. Green indicates VASP; blue, DAPI (nuclei). Scale bar=5 μm. We are grateful to Drs Maria Grant and Sergio Li Calzi, University of Florida, Gainesville, for providing this figure.

Figure 4

Schematic of a blood vessel showing release of the chemokine SDF-1 at the site of injury. SDF-1 induces the heme-degrading enzyme HO-1 in EPC, resulting in the release of CO, which induces redistribution of VASP at the leading edge of EPC, promoting migration and vascular repair.

Figure 5

HO-1–dependent and –independent regulation of VEGF and IL-8 synthesis. In human microvascular endothelial cells, induction of VEGF synthesis by CoPPIX and PGJ2 is dependent on HO-1. However, the same stimuli enhance IL-8 expression independently of HO-1. Cobalt chloride (CoCl2), which increases HIF-1 stability, also strongly induces HO-1 and stimulates VEGF synthesis through HIF-1 but not HO-1. In these microvascular endothelial cells, hypoxia does not induce HO-1 but stimulates VEGF through HIF-1.