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HIF ‐1α and HIF ‐2α induce angiogenesis and improve muscle energy recovery
Author(s) -
Niemi Henna,
Honkonen Krista,
Korpisalo Petra,
Huusko Jenni,
Kansanen Emilia,
Merentie Mari,
Rissanen Tuomas T.,
André Helder,
Pereira Teresa,
Poellinger Lorenz,
Alitalo Kari,
YläHerttuala Seppo
Publication year - 2014
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/eci.12333
Subject(s) - angiogenesis , ventricle , stimulation , skeletal muscle , neovascularization , perfusion , ischemia , medicine , hypoxia (environmental) , endocrinology , cardiology , chemistry , organic chemistry , oxygen
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 ( HIF s) upregulate the expression of angiogenic mediators together with genes involved in energy metabolism and recovery of ischaemic 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 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 31 P ‐magnetic resonance spectroscopy ( 31 P ‐ MRS ), respectively. Results HIF ‐1α and HIF ‐2α 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, A d HIF ‐1α enhanced the recovery of ischaemic 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 A d HIF ‐1α and A d HIF ‐2α 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.