HIF-1α and HIF-2α induce angiogenesis and improve muscle energy recovery

Background Cardiovascular patients suffer from reduced blood flow leading to ischaemia and impaired tissue metabolism. Unfortunately, an increasing group of elderly patients cannot be treated with current revascularization methods. Thus, new treatment strategies are urgently needed. Hypoxia-inducible factors (HIFs) upregulate the expression of angiogenic mediators together with genes involved in energy metabolism and recovery of ischaemic tissues. Especially, HIF-2 alpha is a novel factor, and only limited information is available about its therapeutic potential. Methods Gene transfers with adenoviral HIF-1 alpha and HIF -2 alpha were performed into the mouse heart and rabbit ischaemic hindlimbs. Angiogenesis was evaluated by histology. Left ventricle function was analysed with echocardiography. Perfusion in rabbit skeletal muscles and energy recovery after electrical stimulation induced exercise were measured with ultrasound and P-31-magnetic resonance spectroscopy (P-31-MRS), respectively. Results HIF-1 alpha and HIF-2 alpha gene transfers increased capillary size up to fivefold in myocardium and ischaemic skeletal muscles. Perfusion in skeletal muscles was increased by fourfold without oedema. Especially, AdHIE-1 alpha enhanced the recovery of ischaemic muscles from electrical stimulation-induced energy depletion. Special characteristic of HIF-2 alpha gene transfer was a strong capillary growth in muscle connective tissue and that HIE-2 alpha. gene transfer maintained left ventricle function. Conclusions We conclude that both AdHIF-1 alpha and AdHIF-2 alpha gene transfers induced beneficial angiogenesis in vivo. Transient moderate increases in angiogenesis improved energy recovery after exercise in ischaemic muscles. This study shows for the first time that a moderate increase in angiogenesis is enough to improve tissue energy metabolism, which is potentially a very useful feature for cardiovascular gene therapy.