Abstract 10827: Role of Macrophage-derived Hif-1α as a Mediator of Vascular Remodeling
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. Our previous study showed that cuff injury of the femoral artery induced peri-arterial hypoxia and intimal thickening, and that T cell-specific hypoxia-inducible factor 1α (HIF-1α) inhibits excessive vascular remodeling. The purpose of this study is to clarify the role of macrophage-specific HIF-1α on 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 HIF-1α KO mice was significantly suppressed, compared to that seen in WT mice. Immunohistochemical staining showed the infiltration of macrophages within the adventitia was significantly decreased in HIF-1α KO mice. Second, thioglycollate-induced macrophages were isolated from peritoneal cavities of HIF-1α KO and WT mice, after which migration assays were performed that showed decreased macrophage migration in HIF-1α KO mice. Isolated macrophages were then cultured for 24 hours in HMGB-1, and then ELISA was used to measure concentration of inflammatory and atherosclerosis-related cytokines. HIF-1α KO mice macrophages had significantly less IL-6, TNF-α, ICAM-1, VCAM-1 and COX-2 when compared to WT mice. RT-PCR gene expression of these inflammatory cytokines was similarly decreased in KO macrophages compared to WT. Third, the aforementioned inflammatory cytokines were suppressed and M2-gene expression increased in wire-injured arteries of HIF-1α KO mice.
Conclusions ; Our results show that the macrophage-specific HIF-1α plays a positive role in vascular remodeling after arterial injury in mice. Macrophage-derived HIF-1α may alter vascular remodeling via a variety of inflammatory cytokines, including IL-6, TNF-α, ICAM-1, VCAM-1 and COX-2. Modulation of macrophage-derived HIF-1α may prevent excessive vascular remodeling, thereby offering a potential therapeutic target for vascular disease.
- © 2012 by American Heart Association, Inc.