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

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 programmes. Human endurance and resistance training datasets generated exercise mode specific angiogenic neighbourhoods, showing that canonical mediators, including VEGF-related signalling, occupy divergent network contexts across training modes. Using rat models designed to emphasise 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 translated 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 remodelling, vessel-matrix interaction and coordinated endothelial-matrix programmes, whereas shear-dominant stimuli produced capillary expansion without comparable matrix-remodelling network activation or improvement in fatigue resistance. Hub-set signatures, rather than individual genes, better linked transcriptional remodelling 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 prioritise pro-functional angiogenic stimuli.