Expression of HIF-1α in injured arteries controls SDF-1α-Mediated neointima formation in apolipoprotein E-deficient mice

Objective-Hypoxia-inducible factor (HIF)-1 alpha is the regulatory subunit of a transcriptional complex, which controls the recruitment of multipotent progenitor cells and tissue repair in ischemic tissue by inducing stromal cell- derived factor (SDF)-1 alpha expression. Because HIF-1 alpha can be activated under normoxic conditions in smooth muscle cells (SMCs) by platelet products, we investigated the role of HIF-1 alpha in SDF-1 alpha-mediated neointima formation after vascular injury. Methods and Results-Wire-induced injury of the left carotid artery was performed in apolipoprotein E-deficient mice. HIF-1 alpha expression was increased in the media as early as 1 day after injury, predominantly in SMCs. Nuclear translocation of HIF-1 alpha and colocalization with SDF-1 alpha was detected in neointimal cells after 2 weeks. HIF-1 alpha mRNA expression was induced at 6 hours after injury as determined by real-time RT-PCR. Inhibition of HIF-1 alpha expression by local application of HIF-1 alpha-siRNA reduced the neointimal area by 49% and significantly decreased the neointimal SMCs content compared with control- siRNA. HIF-1 alpha and SDF-1 alpha expression were clearly diminished in neointimal cells of HIF-1 alpha-siRNA treated arteries. Conclusions-HIF-1 alpha expression is directly involved in neointimal formation after vascular injury and mediates the upregulation of SDF-1 alpha, which may affect the stem cell-based repair of injured arteries.