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Chronic blockade of VEGFR‐2 reveals negative feedback regulation of VEGF in exercising muscles of mice
Author(s) -
Pryor Janelle S.,
Adair Thomas H.
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.a528-c
Subject(s) - angiogenesis , endocrinology , hypoxia (environmental) , blockade , medicine , skeletal muscle , vegf receptors , vascular endothelial growth factor , treadmill , downregulation and upregulation , hif1a , gastrocnemius muscle , conditioning , biology , chemistry , receptor , oxygen , biochemistry , organic chemistry , gene , statistics , mathematics
Exercise conditioning causes VEGF‐mediated angiogenesis in skeletal muscle. Prior studies indicate that VEGF mRNA increases initially (days 1–7) in response to exercise‐induced hypoxia, then returns to nearly normal levels after 14–28 days after capillarity has increased and normoxic conditions have been achieved. This temporal relation between muscle capillarity and VEGF expression suggests that VEGF production may be subject to negative feedback control. To test this hypothesis, we used a VEGFR‐2 inhibitor, PTK787 (Novartis), to prevent angiogenesis in skeletal muscle during exercise conditioning, i.e., to “open” the negative feedback loop. Male C57BL/6J mice were dosed with PTK787 or vehicle, and run on a motorized rodent treadmill for 1 hr/day; age‐matched cage‐confined mice dosed with PTK787 or vehicle served as control groups. mRNA expression in gastrocnemius muscles was evaluated from days 1, 4, 7 and 14. VEGF and VEGFR‐1 expression were significantly higher in PTK787‐exercise mice compared to cage‐confined mice at all time points, whereas expression returned to near normal levels in the vehicle‐exercise mice by day 14. Because VEGF and VEGFR‐1 are known to be upregulated by hypoxia, the results suggest that blocking the actions of VEGF impairs adaptation of muscles to exercise conditioning, thus support our primary hypothesis that VEGF is subject to negative feedback control. NHLBI (HL‐51971)