School of Kinesiology and Health Science, Angiogenesis Research Group, York University, Toronto, ON, Canada.
Division of Exercise Physiology & Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, WV, USA.
Acta Physiol (Oxf). 2015 Jul;214(3):349-60. doi: 10.1111/apha.12463. Epub 2015 Feb 26.
The source of vascular endothelial growth factor-A (VEGF-A) may influence vascular function. Exercise-induced vascular growth has been attributed to elevated metabolic demand and to increased blood flow, involving the production of VEGF-A by skeletal muscle and by endothelial cells respectively. We hypothesized that muscle-derived VEGF-A is not required for vascular adaptations to blood flow in skeletal muscle, as this remodelling stimulus originates within the capillary.
Myocyte-specific VEGF-A (mVEGF(-/-) ) deleted mice were treated for 7-21 days with the vasodilator prazosin to produce a sustained increase in skeletal muscle blood flow.
Capillary number increased in the extensor digitorum longus (EDL) muscle in response to prazosin in wild type but not mVEGF(-/-) mice. Prazosin increased the number of smooth muscle actin-positive blood vessels in the EDL of wild-type but not mVEGF(-/-) mice. The average size of smooth muscle actin-positive blood vessels also was smaller in knockout mice after prazosin treatment. In response to prazosin treatment, VEGF-A mRNA was elevated within the EDL of wild-type but not mVEGF(-/-) mice. Ex vivo incubation of wild-type EDL with a nitric oxide donor increased VEGF-A mRNA. Likewise, we demonstrated that nitric oxide donor treatment of cultured myoblasts stimulated an increase in VEGF-A mRNA and protein.
These results suggest a link through which flow-mediated endothelial-derived signals may promote myocyte production of VEGF-A. In turn, myocyte-derived VEGF-A is required for appropriate flow-mediated microvascular remodelling. This highlights the importance of the local environment and paracrine interactions in the regulation of tissue perfusion.
血管内皮生长因子 A（VEGF-A）的来源可能会影响血管功能。运动引起的血管生长归因于代谢需求的增加和血流量的增加，分别涉及到骨骼肌和内皮细胞产生 VEGF-A。我们假设，肌肉来源的 VEGF-A 对于血流对骨骼肌的血管适应不是必需的，因为这种重塑刺激源起源于毛细血管内。
使用血管扩张剂普萘洛尔（prazosin）对肌细胞特异性 VEGF-A（mVEGF(-/-)）缺失小鼠进行 7-21 天的处理，以产生骨骼肌血流量的持续增加。
在野生型小鼠中，普萘洛尔可引起伸趾长肌（EDL）中毛细血管数量增加，但在 mVEGF(-/-) 小鼠中则不然。普萘洛尔增加了野生型小鼠 EDL 中平滑肌肌动蛋白阳性血管的数量，但在 mVEGF(-/-) 小鼠中则不然。敲除小鼠在接受普萘洛尔治疗后，平滑肌肌动蛋白阳性血管的平均大小也较小。在接受普萘洛尔治疗后，野生型小鼠的 EDL 中 VEGF-A mRNA 升高，但 mVEGF(-/-) 小鼠则不然。体外培养野生型 EDL 与一氧化氮供体孵育可增加 VEGF-A mRNA。同样，我们证明了一氧化氮供体处理培养的成肌细胞可刺激 VEGF-A mRNA 和蛋白的增加。
这些结果表明，通过内皮衍生的信号可以促进肌细胞产生 VEGF-A，从而建立了一种联系。反过来，肌细胞来源的 VEGF-A 是适当的血流介导的微血管重塑所必需的。这突出了局部环境和旁分泌相互作用在调节组织灌注中的重要性。
