Metabolic regulation of exercise-induced angiogenesis

Abstract

Skeletal muscle relies on an ingenious network of blood vessels, which ensures optimal oxygen and nutrient supply. An increase in muscle vascularization is an early adaptive event to exercise training, but the cellular and molecular mechanisms underlying exercise-induced blood vessel formation are not completely clear. In this review, we provide a concise overview on how exercise-induced alterations in muscle metabolism can evoke metabolic changes in endothelial cells (ECs) that drive muscle angiogenesis. In skeletal muscle, angiogenesis can occur via sprouting and splitting angiogenesis and is dependent on vascular endothelial growth factor (VEGF) signaling. In the resting muscle, VEGF levels are controlled by the estrogen-related receptor γ (ERRγ). Upon exercise, the transcriptional coactivator peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC1α) orchestrates several adaptations to endurance exercise within muscle fibers and simultaneously promotes transcriptional activation of Vegf expression and increased muscle capillary density. While ECs are highly glycolytic and change their metabolism during sprouting angiogenesis in development and disease, a similar role for EC metabolism in exercise-induced angiogenesis in skeletal muscle remains to be elucidated. Nonetheless, recent studies have illustrated the importance of endothelial hydrogen sulfide and sirtuin 1 (SIRT1) activity for exercise-induced angiogenesis, suggesting that EC metabolic reprogramming may be fundamental in this process. We hypothesize that the exercise-induced angiogenic response can also be modulated by metabolic crosstalk between muscle and the endothelium. Defining the underlying molecular mechanisms responsible for skeletal muscle angiogenesis in response to exercise will yield valuable insight into metabolic regulation as well as the determinants of exercise performance.

Exercising for Insulin Sensitivity – Is There a Mechanistic Relationship With Quantitative Changes in Skeletal Muscle Mass?

“…Irrefutably, PGC-1α transcription is likely one of the main drivers of mitochondrial biogenesis ( Tiraby and Langin, 2005 ) and has been shown to play a significant role in microvascular reactivity and adaptations, through eNOS phosphorylation and vascular endothelial growth factor (VEGF) transcription pathways ( Arany et al, 2008 ; Chinsomboon et al, 2009 ; Baldelli et al, 2014 ). Moreover, PGC-1α transcription has been shown to reflect Hypoxia Inducible Factor-1α (HIF-1α) activity, hence SM local O 2 demand ( Gorski and De Bock, 2019 ). Indeed, endurance exercise generates continuous blood flow elevation toward SM for adequate O 2 and substrate delivery ( Andersen and Saltin, 1985 ).…”

Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4+ endothelial cells

“…Increased muscle capillary density should improve blood-tissue exchange properties by increasing the surface area for oxygen diffusion or nutrient uptake as well as faster elimination of toxic waste products. Trained muscle indeed exhibits higher oxygen exchange capacity and improved glucose uptake ( Gorski and De Bock, 2019 ; Prior et al., 2004 ). The increase in muscle vascularization is an early adaptive event in response to exercise ( Andersen and Henriksson, 1977 ; Waters et al., 2004 ), but the exact mechanisms through which exercise promotes angiogenesis are poorly understood.…”

Microvessel Density: Integrating Sex-Based Differences and Elevated Cardiovascular Risks in Metabolic Syndrome

“…These findings suggest that exercise regimens are most effective when combined with dietary interventions, and with current treatment plans, men may experience a greater benefit with lifestyle changes. Nonetheless, many studies consistently find that exercise promotes the release of VEGF and other pro-angiogenic factors, regardless of sex [101]. This upregulation may induce angiogenesis in skeletal muscle, increasing MVD and overall circulation.…”