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Critical role of HIF1α and HIF2α in stretch‐induced angiogenesis
Author(s) -
Doyle Jennifer Lynn,
Milkiewicz Malgorzata,
Fudalewski Tom,
Haas Tara L
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a14-a
Subject(s) - angiogenesis , downregulation and upregulation , chemistry , hsp90 , hypoxia (environmental) , in vivo , endocrinology , microbiology and biotechnology , medicine , cancer research , biology , heat shock protein , biochemistry , gene , organic chemistry , oxygen
Hypoxia Inducible Factors, HIF1α and HIF2α are transcription factors responsible for upregulation of many genes involved in angiogenesis. Previously we demonstrated increased HIF1,2α mRNA levels in response to muscle stretch. We hypothesize that HIF1,2α are critical for muscle stretch induced angiogenesis and reduction of HIF levels will attenuate this response. A geldanamycin‐derived HSP90 inhibitor, 17‐DMAG, was used to destabilize HIF protein. 17‐DMAG efficacy in endothelial cells was confirmed as exposure to 17‐DMAG (3μM) significantly reduced the cobalt‐stimulated levels on HIF1, 2α and VEGF protein as assessed by western blotting. To stimulate stretch induced angiogenesis in vivo , rat extensor digitorium longus (EDL) muscles were overloaded through removal of the tibialis anterior. EDL were treated with 17‐DMAG (12.5mg/ml) or vehicle continuously via osmotic pump with 17‐DMAG‐treated muscles having decreased HIF1, 2α protein. Capillary to fibre (C:F) ratio was 1.47±0.04 and 1.36±0.06 for vehicle and 17‐DMAG treated unstretched muscles, respectively. After 14 days of overload, C:F was increased to 1.93±0.10 in vehicle treated but this increase was attenuated significantly in overload + 17‐DMAG muscles (1.36±0.05). These results indicate a significant role for HIFs in stretch‐induced angiogenesis distinct from their well defined roles in hypoxia stimulated angiogenesis. Funding by CIHR.