AngioNet: a systems biology approach to regulation of microvascular remodeling in response to skeletal muscle...

Exercise remodels skeletal muscle microvasculature, yet the transcriptional programs that distinguish functionally meaningful angiogenesis from stochastic increases in capillary number remain unclear. Here, we integrate human exercise transcriptomics with reductionist rat models to develop AngioNet, a network-based framework that resolves stimulus-specific angiogenic programs. Human endurance and resistance training datasets generated exercise mode-specific angiogenic neighborhoods, showing that canonical mediators, including VEGF-related signaling, occupy divergent network contexts across training modes. Using rat models designed to emphasize mechanical or metabolic exercise stimuli, we highlight the multitude of interactive signals capable of expanding the capillary network. However, not all microvascular expansion promotes improved oxygen delivery dynamics that translate to improvements in fatigue resistance. This functional divergence was explained by local capillary supply and distribution rather than capillary number alone. Overlaying rat transcriptomes onto AngioNet revealed that functional gains preferentially engaged extracellular matrix remodeling, vessel-matrix interaction, and coordinated endothelial-matrix programs, whereas shear-dominant stimuli produced capillary expansion without comparable matrix-remodeling network activation or improvement in fatigue resistance. Hub-set signatures, rather than individual genes, better linked transcriptional remodeling to local capillary supply area, predicted Po₂, and fatigue resistance. AngioNet therefore provides a mechanistically grounded framework to interpret heterogeneity in exercise-induced vascular adaptation and prioritize profunctional angiogenic stimuli.NEW & NOTEWORTHY We constructed exercise mode-specific angiogenic interaction networks (AngioNets) from endurance and resistance training human datasets. Overlapping stimulus-resolved rat transcriptomes onto these AngioNets, we showed that it is possible to promote angiogenesis through multiple stimuli, yet only a subset led to functional improvement. This divergence is explained by changes in local capillary supply, rather than gross capillary number. Across both human AngioNets, hub-set activity linked transcriptomic programs to microvascular structure, modeled tissue PO₂, and fatigue resistance.