VEGFA Induction in Skeletal Muscle Under Hypoxia and Exercise: A Review of the Epigenetic Role of H3K27me3

Abstract

Skeletal muscle adapts through various structural and molecular changes that support vascular remodelling. Among these, angiogenesis enhances capillary density and improves oxygen and nutrient delivery to active muscle fibres. Vascular endothelial growth factor A (VEGFA) is a key regulator of this process and is robustly induced in skeletal muscle during exercise, largely via activation of Hypoxia-inducible Factor 1-alpha (HIF-1α). However, HIF-1α activity diminishes with prolonged training, suggesting the need for additional mechanisms to sustain VEGFA expression. This review synthesizes findings from vascular biology, epigenetics, and exercise physiology to explore the potential role of histone modification H3K27me3 in regulating VEGFA expression during hypoxic and exercise-induced stress in skeletal muscle. Evidence from endothelial cells indicates that H3K27me3, a repressive histone mark, can be removed by the demethylase JMJD3 to enable VEGFA transcription in response to hypoxia. Although this mechanism is well characterized in vascular tissue, recent studies suggest similar epigenetic changes occur in skeletal muscle, particularly at promoters of exercise-responsive genes like PGC-1α. These findings support the hypothesis that epigenetic regulation through H3K27me3 demethylation may contribute to sustained VEGFA expression as HIF-1α activity declines with training. However, direct evidence in human skeletal muscle remains limited. Histone demethylation may represent a key mechanism supporting angiogenesis in skeletal muscle under exercise and hypoxic conditions. These epigenetic mechanisms may also be relevant for skeletal muscle adaptation to exercise.