Abstract
Skeletal muscle overload induces the expression of angiogenic factors such as vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2, leading to new capillary growth. We found that the overload-induced increase in angiogenesis, as well as increases in VEGF, MMP-2 and MT1-MMP transcripts were abrogated in muscle VEGF KO mice, highlighting the critical role of myocyte-derived VEGF in controlling this process. The upstream mediators that contribute to overload-induced expression of VEGF have yet to be ascertained. We found that muscle overload increased angiotensinogen expression, a precursor of angiotensin (Ang) II, and that Ang II signaling played an important role in basal VEGF production in C2C12 cells. Furthermore, matrix-bound VEGF released from myoblasts induced the activation of endothelial cells, as evidenced by elevated endothelial cell phospho-p38 levels. We also found that exogenous Ang II elevates VEGF expression, as well as MMP-2 transcript levels in C2C12 myotubes. Interestingly, these responses also were observed in skeletal muscle endothelial cells in response to Ang II treatment, indicating that these cells also can respond directly to the stimulus. The involvement of Ang II in muscle overload-induced angiogenesis was assessed. We found that blockade of AT1R-dependent Ang II signaling using losartan did not attenuate capillary growth. Surprisingly, increased levels of VEGF protein were detected in overloaded muscle from losartan-treated rats. Similarly, we observed elevated VEGF production in cultured endothelial cells treated with losartan alone or in combination with Ang II. These studies conclusively establish the requirement for muscle derived VEGF in overload-induced angiogenesis and highlight a role for Ang II in basal VEGF production in skeletal muscle. However, while Ang II signaling is activated following overload and plays a role in muscle VEGF production, inhibition of this pathway is not sufficient to halt overload-induced angiogenesis, indicating that AT1-independent signals maintain VEGF production in losartan-treated muscle.
Highlights
Communication between skeletal muscle fibers and the microcirculation is critical to ensure that the metabolic demands of the muscle are met
To assess the importance of muscle Vascular endothelial growth factor (VEGF) to overloadinduced angiogenesis, we examined mRNA levels of proangiogenic factors VEGF, Matrix metalloproteinase (MMP)-2 and MT1-MMP after 7, and capillary growth after 14, days of extensor digitorum longus (EDL) overload in wildtype or muscle VEGF-deficient mice
We provided conclusive evidence that muscle-derived VEGF is an absolute requirement for overload-induced skeletal muscle angiogenesis
Summary
Communication between skeletal muscle fibers and the microcirculation is critical to ensure that the metabolic demands of the muscle are met. Angiogenesis, the process of blood vessel growth from pre-existing vessels, is induced in response to increased muscle activity, through the coordinated actions of growth factors and matrix degrading enzymes [1,2,3]. Matrix metalloproteinase (MMP)-2, which facilitates basement membrane degradation and capillary sprouting, is elevated in rodent muscle subjected to overload or electrical stimulation [2,4] and in human muscle following exercise training [5]. Reduction of VEGF signaling, either through competitive blockade of VEGFR activation (VEGF-TRAP) or by conditional deletion of myocyte VEGF, prevents capillary growth in response to muscle overload or exercise training, respectively [12,13]
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