Idiopathic osteonecrosis of the femoral head (IONF) is known to be caused by tissue ischemia, which is mainly associated with high-dose glucocorticoid (GC) used for the treatments of systemic autoimmune diseases. However, precise pathological mechanisms of IONF remain unclear. We first found that hypoxia-inducible factor (HIF) -1alpha, a major transcription factor rapidly induced under hypoxic conditions, was highly expressed on endothelial cells of femoral head in patients with IONF. Transfection of HIF-1alpha induced p21-mediated arrest of cell cycle and subsequent apoptosis in endothelial cells. High dose GC also induced cell cycle arrest and apoptosis. Furthermore, there were additional effects between HIF-1alpha and high dose GC for the growth arrests and apoptosis of the cells. However, C-type natriuretic peptide (CNP) inhibited both cell cycle arrest and apoptosis of the endothelial cells in a concentration-dependent manner. There results indicate that hypoxia and high-dose GC play a pivotal role for vascular injury and that CNP could have a potential to protect the vascular injury seen in patients with IONF.