Abstract 15784: Macrophage-Specific Hypoxia-Inducible Factor (HIF)-1a-Deficient Mice Suppress the Vascular Remodeling and Regulate M2 Macrophage Polarization
Background and Purpose: Excessive vascular remodeling leads to progression of a wide range of vasculopathies, and the immune response to intimal injuries is crucial in this process. This vascular remodeling occurs in the hypoxic microenvironment and is closely related to the immune system. Macrophages play a key role in immunologic-cell-mediated arterial remodeling. In this study, we clarified the role of macrophage-derived hypoxia-inducible factor (HIF-1α) in vascular remodeling
Methods and Results: First, vascular remodeling of the femoral artery was investigated in vivo using myeloid cell-specific Hif-1α deficient mice generated by crossing Hif-1α-floxed mice with LysM Cre mice (KO: LysM-Cre;HIF1-αflox/flox, WT: LysM-Cre;HIF1-α+/+) at 4 weeks after wire injury. Neointimal thickening in KO mice was significantly suppressed, compared to that in WT mice. Immunohistochemical staining showed the infiltration of macrophages within the adventitia was significantly decreased in KO mice.
Second, thioglycollate-induced macrophages were isolated from peritoneal cavities of KO and WT mice. The macrophage migration assays were performed and showed a decreased migration of macrophages in KO mice compared to the WT mice. Isolated macrophages were then cultured for 24 hours in HMGB-1, macrophages in KO mice showed a remarkable decrease in productions of IL-6, TNF-α, ICAM-1, VCAM-1 and COX-2 compared to the WT mice.
Third, the aforementioned inflammatory cytokines were suppressed and M2-gene expression increased in wire-injured arteries of KO mice. To evaluate the phenotypic profile of macrophages, we also conducted an immunohistochemical evaluation. HIF-1α-deficient macrophages positively correlated with the phenotypic profile of M2 macrophages and negatively correlated with that of M1 macrophages.
Conclusions: Our results show that HIF-1α in macrophages plays a crucial role in promoting vascular inflammation and remodeling. As decreasing HIF-1α activity in macrophages may prevent the progression of vascular remodeling, HIF-1α may be a possible therapeutic target in vascular diseases.
- © 2013 by American Heart Association, Inc.