Regulation of Vascularization by Hypoxia‐Inducible Factor 1

Vascularization and vascular remodeling represent critical adaptive responses to tissue hypoxia that are mediated by hypoxia‐inducible factor 1 (HIF‐1). In patients with peripheral arterial disease, these responses are impaired by aging and diabetes, leading to critical limb ischemia and amputation. Intramuscular injection of an adenovirus encoding a constitutively active form of the HIF‐1α subunit (CA5) increases the recovery of blood flow following femoral artery ligation in a mouse model of age‐dependent critical limb ischemia. Intradermal injection of a plasmid encoding CA5 promotes healing of cutaneous wounds in a mouse model of diabetes. In cancer, vascularization is required for tumors to grow beyond microscopic size, a process that involves HIF‐1‐dependent production of angiogenic growth factors. Daily treatment of prostate cancer xenograft‐bearing mice with low‐dose anthracycline (doxorubicin or daunorubicin) chemotherapy inhibits HIF‐1 DNA‐binding activity, HIF‐1‐dependent expression of angiogenic growth factors, mobilization of circulating angiogenic cells, and tumor vascularization, thereby arresting tumor growth.