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Conditional VEGF Gene Deletion in Both Endothelial Cells and Skeletal Myofibers Leads to Exercise Intolerance Accompanied by a Decrease in Body Mass and Cardiac Enlargement
Author(s) -
Sulaeman Alexis,
Fine Janelle,
Wagner Peter,
Breen Ellen
Publication year - 2015
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.29.1_supplement.1050.1
Subject(s) - endocrinology , medicine , vascular endothelial growth factor , chemistry , cre recombinase , skeletal muscle , transgene , genetically modified mouse , biology , vegf receptors , gene , biochemistry
The mechanism by which VEGF‐dependent peripheral vascular function contributes to exercise is unclear. We hypothesized inhibition of VEGF expression in both endothelial cells (EC) and skeletal myofibers leads to capillary regression, impairs muscle function and limits exercise. To test this hypothesis, VEGF gene deletion was tamoxifen‐induced in both EC and myofibers of adult mice that carry the VEGF LoxP , HSA‐CRE‐ER T2 and PDGFb‐iCre‐ER T2 transgenes ( Skm/EC‐VEGF‐/‐ mice ). Additional VEGF LoxP mice carried either the HSA‐Cre‐ER T2 ( SkmVEGF‐/‐ ) or PDGFb‐iCre‐ER T2 ( EC‐VEGF‐/‐ ) transgene or did not express cre recombinase ( WT ). In treadmill running tests, Skm/EC‐VEGF‐/‐ mice showed a 46% decrease in endurance than WT mice (n= 11‐27, p < 0.01). Over the 3‐week post‐tamoxifen period, WT, SkmVEGF‐/‐, and EC‐VEGF‐/‐ mice (but not Skm/EC‐VEGF mice‐/‐) gained weight (WT, 27.4 ± 0.35 g, Skm/EC‐VEGF‐/‐, 25.7 ± 0.68 g; n=18‐48, p < 0.05). Skm/EC‐VEGF‐/‐ mice had larger heart to body mass ratios (Skm/EC‐VEGF‐/‐, 6.17 ± 0.23 g/BW; SkmVEGF‐/‐, 5.46 ± 0.14 g/BW; EC‐VEGF‐/‐, 5.46 ± 0.14 g/BW; WT, 5.63 ± 0.10 g/BW, n=18‐48,p < 0.01). Muscle mass, capillary to fiber ratio, fiber area and type in the soleus, plantaris, and gastrocnemius remained unchanged. Ex vivo muscle contractility and fatigue resistance did not differ between WT and Skm/EC‐VEGF‐/‐ soleus, and only the Skm/EC‐VEGF‐/‐ EDL was more fatigue resistant (Skm/EC‐VEGF‐/‐, 188.4 ± 6.57 s; WT, 157.48 ± 9.52 s, n= 11‐14, p < 0.01). The data suggests that endurance is limited when VEGF expression is inhibited in both EC and myofibers. This exercise intolerance is not due to muscle capillary regression, but possibly a decrease in body mass and/or cardiac function.