Regulation of Exercise Induced Endothelial Sprout Formation

Capillary sprouting is known to be guided by Dll4/Notch signaling in mouse retina, while maturation of the endothelium is regulated by Dll1 and Tie2. This study investigates the key molecules involved in endothelial sprouting and maturation, and the gene that orchestrates the expression of these targets in skeletal muscle in response to exercise. In exercised mice, Dll1 and Dll4 proteins were decreased with repeated training. Tie2 mRNA was downregulated with 5 days of exercise. The suppression of these molecules may induce destabilization of the endothelium and allow for sprouting to occur. Moreover, FoxO transcription factors have been shown to be anti-angiogenic and may negatively regulate genes involved in sprouting. Both Dll1 and Dll4 expression were not altered with repeated exercise in mice with endothelial cell directed conditional deletion of FoxO1/3a/4 (FoxO∆). We have provided insight into the mechanisms behind the initiation of capillary growth in skeletal muscle induced by exercise.