title: HIF-1α and HIF-2α induce angiogenesis and improve muscle energy recovery.
abstract: 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-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, AdHIF-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 AdHIF-1α and AdHIF-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.
authors.affiliation: Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Niemi
authors.forename: Krista
authors.initials: K
authors.lastname: Honkonen
authors.forename: Petra
authors.initials: P
authors.lastname: Korpisalo
authors.forename: Jenni
authors.initials: J
authors.lastname: Huusko
authors.forename: Emilia
authors.initials: E
authors.lastname: Kansanen
authors.forename: Mari
authors.initials: M
authors.lastname: Merentie
authors.forename: Tuomas T
authors.initials: TT
authors.lastname: Rissanen
authors.forename: Helder
authors.initials: H
authors.lastname: André
authors.forename: Teresa
authors.initials: T
authors.lastname: Pereira
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000494:pharmacology*; D002196:Capillaries / Q000502:physiology; D003331:Coronary Vessels / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006614:Hindlimb / Q000098:blood supply; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000494:pharmacology*; D007511:Ischemia / Q000503:physiopathology / Q000628:therapy; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011817:Rabbits; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: Angiogenesis; HIF-1α; HIF-2α; gene therapy; magnetic resonance spectroscopy; skeletal muscle energy metabolism; ultrasound imaging