Dual role of vascular endothelial growth factor family members and angiomotion in vascular and muscular plasticity during rodent skeletal muscle remodeling

骨骼肌能迅速适应功能需求的变化，具有显著的可塑性，其毛细血管和肌纤维特性的变化证明了这一点。肌纤维产生血管内皮生长因子-A(VEGF-A)，它是肌肉血管生成的关键启动因子，即毛细血管的从头合成。血管内皮生长因子-A还确保已建立的毛细血管的维持。在骨骼肌重建过程中，肌纤维主要通过调节血管内皮生长因子-A的表达来调节肌肉的毛细血管，进而促进血管生成或诱导血管倒退。然而，肌纤维、血管内皮生长因子-A与毛细血管之间的关系可能更为复杂。最近的证据表明，肌纤维继发于血管内皮生长因子-A的表达对肌肉毛细血管的调节可以控制肌纤维收缩表型的变化。此外，最近的数据表明，血管内皮生长因子-A也可以影响肌肉细胞的代谢特性。因此，我假设在骨骼肌重建过程中，肌纤维表达的血管内皮生长因子-A将影响其收缩和代谢表型。此外，肌肉毛细血管的退化、维持或刺激不能单独用血管内皮生长因子-A来解释。在血管生成因子中，血管内皮生长因子-B和血管紧张素高表达于骨骼肌。此外，他们的行动不仅限于毛细管控。因此，我假设这些分子除了参与血管生成外，还可能在肌肉细胞重建中发挥作用。我的研究计划的总体目的是研究最初在血管形成过程中描述的血管内皮生长因子-A、血管内皮生长因子-B和血管生成蛋白是否对毛细血管和肌纤维起双重作用。因此，通过作用于内皮细胞和心肌细胞，它们可能对肌肉重塑至关重要。NSERC建议中提出的计划将带来新的知识，以了解这些分子在啮齿动物骨骼肌重塑过程中对肌肉和血管可塑性所起的基本作用。

Skeletal muscle rapidly adapts to variations of the functional demand with a remarkable plasticity that can be evidenced by changes in capillarity and myofibres' properties.Myofibres produce vascular endothelial growth factor-A (VEGF-A), a key initiator of muscular angiogenesis, i.e. the de novo synthesis of blood capillaries. VEGF-A also ensures the maintenance of established capillaries. During skeletal muscle remodeling, myofibres could thus adjust muscle capillarity mainly by modulating VEGF-A expression that would in turn either enhance angiogenesis or induce vascular regression.However this relationship between myofibres, VEGF-A and capillaries is likely much more complex. Recent evidences suggest that the modulation of muscle capillarity, secondary to VEGF-A expression by myofibres, could control changes in the myofibres' contractile phenotype. In addition, recent data have shown that VEGF-A could also affect the metabolic properties of muscle cells. I therefore hypothesize that VEGF-A expression by myofibres will affect both their contractile and metabolic phenotypes during skeletal muscle remodeling.Moreover, regression, maintenance or stimulation of muscle capillarity cannot be explained by VEGF-A alone. Among angiogenesis factors, the vascular endothelial growth factor-B and angiomotin are highly expressed in skeletal muscle. Furthermore, their action is not restricted to capillarity regulation only. I thus hypothesize that aside from their involvement in angiogenesis, these molecules could play a role in muscle cells remodeling.The overall aim of my research program is to investigate whether VEGF-A, VEGF-B and angiomotin, initially described during angiogenesis, play a dual role on capillaries and myofibres. Thus, by acting on both endothelial cells and myocytes, they could be of critical importance for muscle remodeling. The program presented in this NSERC proposal will bring new knowledge in understanding the fundamental roles played by these molecules on both muscular and vascular plasticity during rodent skeletal muscle remodeling.