Abstract 17721: Deficiency of Hypoxia Inducible Factor-1α in SM-22α-Expressing Bone Marrow-Derived Cells Alleviates Neointimal Formation Following Wire-induced Vascular Injury
Introduction: It have suggested that activation of Hypoxia Inducible Factor-1α (HIF-1α) links to cell proliferation and resistance to apoptosis in vascular smooth muscle cells (VSMCs) and that its expression is increased by several growth factors and cytokines which play an important role in the development of atherosclerosis and restenosis. However, the contribution of HIF-1α to these diseases is still unclear. We assessed the hypothesis that activation of HIF-1α in SM-22α-expressing vascular cells, which include VSMCs and partly bone marrow-derived cells (BMDCs), leads to vascular remodeling following wire-induced vascular injury.
Methods and Results: Wire-mediated vascular injury was produced in the femoral artery of Hif-1α deficient (KO) mice generated by crossing Hif-1α-floxed mice with SM-22α-Cre mice, and their phenotype was characterized at 4 weeks after the injury. Neointimal thickening in KO mice was significantly suppressed compared to that in control (CNTL) mice, (Neointima/Media ratio: 3.75±0.83 vs. 1.75±0.17, p<0.05). In addition, the production levels of inflammatory molecules induced by the injury such as TNF-α, IL-6 and F4/80 (a surface marker of macrophages) were remarkably decreased at the injured vessels in KO mice. To investigate the contribution of SM-22α-expressing BMDCs to development of the injured vascular remodeling because of SM-22α also expressed in BMDCs, we developed bone marrow-transplanted mice and found that neointimal formation was significantly decreased in the KO even CNTL mice reconstituted with KO bone marrow cells, compared to those with CNTL bone marrow cells (N/M ratio: 2.87±0.26 (BMTCNTL→CNTL) vs. 1.23±0.25 (BMTKO→CNTL) and 1.4±0.23 (BMTKO→KO), P<0.001 and P<0.005, respectively). We could not detect significant difference between CNTL and KO mice reconstituted with CNTL bone marrow cells. Immunohistochemical analyses showed that SM-22α-expressing BMDCs were migrated to the injured vessel walls in bone marrow-transplanted mice reconstituted with the bone marrow cells from SM-22α promoter-driving Cre-EGFP reporter mice.
Conclusion: These results indicate that SM-22α-expressing bone marrow-derived HIF-1α is critical for vascular remodeling after the arterial injury.
- © 2012 by American Heart Association, Inc.