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Murine Double Minute‐2 is a new regulator of physiopathological angio‐adaptation in cardiac and skeletal muscles
Author(s) -
ROUDIER Emilie,
OLFERT Mark I.,
PERRY Mary E.,
BIROT Olivier
Publication year - 2011
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.25.1_supplement.1092.26
Subject(s) - regulator , adaptation (eye) , cardiology , chemistry , medicine , skeletal muscle , biology , neuroscience , biochemistry , gene
Maintenance of the established vasculature and angiogenesis is critical for vascular homeostasis in adults. Murine double minute‐2 (Mdm2) oncoprotein was shown to regulate the expression of the pro‐angiogenic Vascular Endothelial Growth Factor (VEGF) in vitro and in tumors. Here we aimed to determine if Mdm2 regulates muscle angio‐adaptation in vivo . Methods and main results Mdm2 protein positively correlated with high levels of capillarization and VEGF expression in cardiac and skeletal muscles. Mdm2 and VEGF expression, and capillarization were decreased in diabetic skeletal muscle and failing heart. Interestingly, physical exercise prevented or restored such alterations. In transgenic mice with hypomorphic and knockout alleles for Mdm2, muscles possess 20% less capillaries and exercise‐induced VEGF expression is inhibited. Our 3D angiogenesis assay enables us to study the angiogenic activity of endothelial cells in cultured muscle explants. Stimulation of explants with muscle homogenates obtained from exercised animals enhanced endothelial cell migration. This was suppressed in explants obtained from Mdm2 hypomorphic mice or wild‐type animals treated with Mdm2 inhibitor Nutlin‐3. Conclusion We identified a complex relationship between Mdm2 and VEGF that regulates cardiac and skeletal muscle angio‐adaptation. Research support: Natural Sciences and Engineering Research Council of Canada.