Uchida C, Nwadozi E, Hasanee A, Olenich S, Olfert IM, Haas TL. Muscle-derived vascular endothelial growth factor regulates microvascular remodelling in response to increased shear stress in mice. Acta Physiol (Oxf). 2015 Jul;214(3):349-60. doi: 10.1111/apha.12463.
It is well established the muscle cells release factors that provide important information to the local blood vessels. Vascular endothelial growth factor (VEGF) is one such mediator that is released from working muscle cells. It stimulates the growth of new capillaries, so that the metabolically active muscle is supplied with a denser network of blood vessels to improve oxygen and nutrient delivery. However, high levels of blood flow also cause new capillaries to be formed. This is thought to occur through sensing of the mechanical force of blood against the surface of the blood vessel and is independent of metabolic factors. In this study, we hypothesized that VEGF from muscle cells would not be required for flow-dependent capillary growth. We utilized mice that were genetically modified to prevent VEGF production in muscle cells and we found that blood flow-stimulated capillary growth did not occur in the absence of muscle cell-derived VEGF. Further tests demonstrated that blood vessel cells (endothelial cells) release a chemical, nitric oxide, in response to blood flow, which causes muscle cells to produce VEGF. This study illustrates an intricate cross-communication between blood vessels and muscle cells: signals from blood vessels provoke muscle cells to make VEGF, which in turn acts on the blood vessels to stimulate the growth of additional capillaries. This study furthers our understanding of how capillary growth is regulated within skeletal muscle, which can aid in future therapeutic developments to improve blood supply to ischemic muscle.