Expression of HIF-1α in Injured Arteries Controls SDF-1α–Mediated Neointima Formation in Apolipoprotein E–Deficient Mice
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Objective— Hypoxia-inducible factor (HIF)-1α 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)-1α expression. Because HIF-1α can be activated under normoxic conditions in smooth muscle cells (SMCs) by platelet products, we investigated the role of HIF-1α in SDF-1α–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-1α expression was increased in the media as early as 1 day after injury, predominantly in SMCs. Nuclear translocation of HIF-1α and colocalization with SDF-1α was detected in neointimal cells after 2 weeks. HIF-1α mRNA expression was induced at 6 hours after injury as determined by real-time RT-PCR. Inhibition of HIF-1α expression by local application of HIF-1α-siRNA reduced the neointimal area by 49% and significantly decreased the neointimal SMCs content compared with control-siRNA. HIF-1α and SDF-1α expression were clearly diminished in neointimal cells of HIF-1α-siRNA treated arteries.
Conclusions— HIF-1α expression is directly involved in neointimal formation after vascular injury and mediates the upregulation of SDF-1α, which may affect the stem cell–based repair of injured arteries.