Effect of hypoxia-inducible factor 1 on vascular endothelial growth factor expression in exercised human skeletal muscle: a systematic review and meta-analysis

• Published in: American Journal of Physiology: Cell Physiology Vol. 329; no. 1; pp. C272 - C282
• Main Authors: Aragón-Vela, Jerónimo, Casuso, Rafael A.
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.07.2025
• Subjects: Angiogenesis; Exercise; Exercise - physiology; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Meta-analysis; Muscle Contraction; Muscle, Skeletal - metabolism; Musculoskeletal system; Neovascularization, Physiologic; Physical fitness; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Skeletal muscle; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; HIF-1; hypoxia; training; VEGF; angiogenesis
• DOI: 10.1152/ajpcell.00297.2025
• ISSN: 0363-6143; 1522-1563

This analysis shows that both HIF-1α mRNA and protein levels are significantly elevated in skeletal muscle following dynamic exercise. However, the absence of a clear relationship between HIF-1α mRNA and the mRNA levels of its downstream target VEGF suggests that HIF-1α mRNA expression alone may not reliably reflect its regulatory role in VEGF transcription in response to exercise. Given the limited number of human studies examining posttranslational regulation of HIF-1α, its precise contribution to VEGF-mediated angiogenic signaling in exercised skeletal muscle remains uncertain. Within contracting human skeletal muscle (SKM), oxygen pressure significantly drops, which has been linked to the activation of a signaling cascade mediated by hypoxia-inducible factor 1α (HIF-1α). This cascade leads to SKM angiogenesis through vascular endothelial growth factor (VEGF). However, the role of HIF-1α in exercise-induced VEGF expression within SKM remains unclear. In this study, we systematically reviewed the literature to quantitatively synthesize all available evidence on HIF-1α activation in exercised human muscle. We identified 21 studies providing 39 effect sizes of pre- and postexercise SKM HIF-1α data from 235 subjects, with 15 of them also presenting data on VEGF mRNA levels. HIF-1α mRNA increased in response to high-intensity and resistance exercise, regardless of participants’ physical fitness levels. Notably, meta-regression showed that exercise-induced VEGF expression is not modulated by HIF-1α mRNA levels. Similarly, when plotting exercise-induced fold changes of VEGF and HIF-1α, no significant relationship was observed. Our findings demonstrate that HIF-1α is expressed in contracting SKM. However, the role of HIF-1α in the exercise-induced angiogenic response remains unclear, as most of the available evidence is limited to transcriptional data. NEW & NOTEWORTHY This analysis shows that both HIF-1α mRNA and protein levels are significantly elevated in skeletal muscle following dynamic exercise. However, the absence of a clear relationship between HIF-1α mRNA and the mRNA levels of its downstream target VEGF suggests that HIF-1α mRNA expression alone may not reliably reflect its regulatory role in VEGF transcription in response to exercise. Given the limited number of human studies examining posttranslational regulation of HIF-1α, its precise contribution to VEGF-mediated angiogenic signaling in exercised skeletal muscle remains uncertain.