Muscle-derived vascular endothelial growth factor regulates microvascular remodelling in response to increased shear stress in mice

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.

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.

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.