H-type vessels are regulated by hypoxia-inducible factor (HIF-1α) and vascular endothelial cell growth factor (VEGF). HIF-1α is a transcription factor that mediates cell activity in response to changes in oxygen and controls physiological and pathological neovascularization [
48]. VEGF is a major regulator of angiogenesis and promotes migration and diffusion of endothelial cells (EC) [
26]. The stability and activity of the HIF-1α subunit is regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, and phosphorylation [
74]. Under normal oxygen conditions, PHD hydroxylated proline (Pro) residues are present in ODDD (Pro 402 and 564 of HIF1α, Pro 405 and 531) of HIF2α induce ubiquitin reaction of E3 ubiquitin ligase Von Hippel-Lindau protein (pVHL), mediated by 26S proteasome, resulting in HIF-1α degradation via the ubiquitin proteasome pathway [
75]. During hypoxia or iron deficiency, PHDs are inactivated, HIF-1α hydroxylation is inhibited, HIF-1α subunits become stable and dimerize with HIF-1β, forming an HIF complex via ARnt-mediated transfer from cytoplasmic to nuclear, possibly interacting with HIF-αβ transcription complex to further activate hypoxia. HIF-αβ heterodimer complexes bind to hypoxia response elements (HREs) containing the consensus core sequence RCGTG (R: A/G) of target gene promoter region and p300/CBP to regulate the expression of target genes [
76]. However, in steroid-induced necrosis of the femoral head, the main target gene of HIF-1α is VEGF [
77]. In animal experiments related to glucocorticoids and H-type blood vessels, Laneet al.’s [
78] study showed that the number of H-type blood vessels in the distal metaphyseal of femur of mice in the glucocorticoid-treated group (fed 4 mg/L/d Dex, the duration was 4 weeks and the first, 14th and 28th days were observed) was significantly reduced compared with the normal control group and the treatment group. In the femoral head, osteoclasts increased, osteoblasts decreased, HIF-1α and VEGF expression decreased, and the decrease of HIF-1α expression further resulted in the decrease of the number of H subtype vessels. Weinstein et al. [
73] used methylprednisolone(MPS) (Full implantable drug delivery system release 2.1 mg/kg/d) to intervene mice to observe the molecular, biomechanical, cellular and vascular changes of femur, and found that after 14 days of intervention, the expression of hypoxia-inducing factor (HIF-1α) and vascular endothelial growth factor (VEGF) in the femoral head, the number of osteoblasts, the rate of bone formation and the strength of bone decreased, while osteoclasts increased. In addition, the decrease of Hif-1α and VEGF expression, bone vessels and strength preceded the loss of bone mass and the deterioration of microstructure, which made the femoral head prone to collapse. Yu al. [
79] used MPS combined with LPS to perform SINFH modeling. Rats were injected intraperitoneally with lipopolysaccharides (LPS 20 μg/kg) for two consecutive times at an interval of 24h each time. After the last injection 24h later, meprednisolone (40 mg/kg) was alternately injected into both gluteus muscles for three times, at an interval of 24 h each time. In the desferramine group, intraperitoneal injection of desferramine mesylate (250 mg/kg) was administered. After 6 weeks, Micro-CT analysis was used to observe the changes in the microstructure of the femoral head, HE staining was used to observe the pathological changes of the femoral head, and immunofluorescence staining was used to analyze the changes in H-type blood vessels in the femoral head. RT-PCR was used to analyze the expression of Hif-1α/VEGF signaling axis related factors in the femoral head. The results showed that the expressions of Hif-1α and VEGF were significantly lower than those in the injection group, and H-type angiogenesis was reduced, bone trabeculae were thin, and microfractures occurred. This was because the degradation of HIF-1α could be inhibited by the reduction of intracellular Fe2
+ concentration and the inhibition of PHD activity.