The molecular networks involved in physiological (exercise-induced) angiogenesis are not well understood. There are a large number of ‘key’ angiogenic factors discussed within the literature that are believed to be important in the regulation of capillary growth, but we are not yet able to establish a functional link between these key-regulators and the phenotypic response of skeletal muscle following exercise. Therefore, we utilised a systems biology approach to examine chronic human exercise data to derive angiogenic networks for commonly reported angiogenic regulators. These human derived angiogenic gene sets were then used to characterise known animal models of angiogenesis to establish their viability for translational angiogenic research, and in addition explore potentially unique angiogenic pathways involved in mechanotransduction-driven remodelling. Endurance and resistance training have a largely similar global endpoint phenotype, with increased extracellular matrix remodelling proteins and inflammatory mediated signalling. In animals, treatment with prazosin (a vasodilator that induces elevated shear stress) there was no commonality of gene signature with overload driven angiogenesis (following surgical agonist ablation), and no evident overlap with endurance or resistance derived angiogenic networks from humans. Indirect electrical stimulation in animals had a largely similar angiogenic genotype to human endurance and resistance exercise, with little differentiation between frequencies (4, 10, 40Hz). The P53 pathway plays an important role in the inhibition of angiogenesis, inhibition of mTOR/IGF-a pathway, and mitochondrial biogenesis; and shows some promise in unravelling the fine control elements of these adaptive responses. The animal models of angiogenesis have suggested a potential role for the histone deacetylase (HDACs) in shear stress-driven angiogenesis, while overload-induced microvascular adaptation appears to be largely cytokine driven.