BACKGROUND:

Cardiovascular patients suffer from reduced blood flow leading to ischemia 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 ischemic tissues. Especially, HIF-2α is a novel factor and only limited information is available about its therapeutic potential.

METHODS:

Gene transfers with adenoviral HIF-1α and HIF-2α were done into the mouse heart and rabbit ischemic 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 31 P-magnetic resonance spectroscopy (31 P-MRS), respectively.

RESULTS:

HIF-1α and HIF-2α gene transfers increased capillary size up to 5-fold in myocardium and ischemic skeletal muscles. Perfusion in skeletal muscles was increased by 4-fold without edema. Especially AdHIF-1α enhanced the recovery of ischemic muscles from electrical stimulation-induced energy depletion. Special characteristic of HIF-2α gene transfer was a strong capillary growth in muscle connective tissue and that HIF-2α gene transfer maintained left ventricle function.

CONCLUSIONS:

We conclude that both AdHIF-1α and AdHIF-2α gene transfers induced beneficial angiogenesis in vivo. Transient moderate increases in angiogesis improved energy recovery after exercise in ischemic 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.