Role of macrophage-derived hypoxia-inducible factor (HIF)-1 as a mediator of vascular remodelling

Excessive vascular remodelling leads to progression of a wide range of vasculopathies, and the immune response to intimal injuries is crucial in this process. This vascular remodelling occurs in the hypoxic microenvironment and is closely related to the immune system. Macrophages play a key role in immunological-cell-mediated arterial remodelling. In this study, we clarified the role of macrophage-derived hypoxia-inducible factor (HIF-1) in vascular remodelling. Wire-induced femoral arterial injury was inflicted in mice lacking the macrophage-specific HIF-1 gene and in their wild-type counterparts. The mutant mice showed both suppressed wire-induced neointimal thickening and decreased infiltration of inflammatory cells in the adventitia, compared with wild-type mice. Studies to clarify the mechanism of restrained vascular remodelling in the mutant mice revealed decreased production of pro-inflammatory cytokines by the activated macrophages and suppressed macrophage migration activity in the mutant mice. Gene expressions of the HIF-1-deficient macrophages positively correlated with the phenotypic profile of M2 macrophages and negatively correlated with that of M1 macrophages. Our results show that HIF-1 in macrophages plays a crucial role in promoting vascular inflammation and remodelling. As decreasing HIF-1 activity in macrophages may prevent the progression of vascular remodelling, HIF-1 may be a possible therapeutic target in vascular diseases.