Chronic blockade of VEGF receptor 2 (VEGFR‐2) causes prolonged increases in VEGF expression in skeletal muscle of treadmill‐exercised mice

Abstract

Long-term exercise causes a VEGF-mediated increase in angiogenesis in skeletal muscle. The VEGF mRNA response consists of an initial large increase in expression (days 1–7), which returns to nearly normal levels after 14–28 days when the muscle capillarity has adapted to the exercise. This temporal relation between muscle capillarity and VEGF expression supports the contention that VEGF production may be regulated by a negative feedback mechanism. Presumably, the increase in capillarity induced by VEGF returns tissue oxygenation to normal, and VEGF expression, in turn, returns to nearly normal levels. To test the hypothesis that VEGF is subject to negative feedback regulation, we attempted to “open” the feedback loop using a VEGF receptor inhibitor, PTK787 (Novartis) to prevent angiogenesis in skeletal muscle during exercise conditioning. Male C57BL/6J mice were treated with PTK787 (50 mg/kg/day, oral), or an equivalent volume of vehicle, and exercised for 1 hr/day at 18 m/min, 10° incline, on a motorized rodent treadmill. After 14 days, VEGF mRNA expression in gastrocnemius muscle was 2-fold higher in mice treated with PTK787 (n=8) compared to exercised mice treated with vehicle (n=4). These results suggest that inhibition of VEGF receptor function in the face of chronically increased metabolic demand leads to chronically elevated expression of VEGF. NHLBI (HL-51971)