Ketosis enhances vascular function, angiogenic signalling and the erythropoietic response to exercise and hypoxia

Regular physical activity improves vascular function and promotes angiogenesis and erythropoiesis, which are further augmented by hypoxia. Early evidence suggests that long-term exogenous ketosis (EK) can enhance vascular function and angiogenesis. However, the acute responses and underlying mechanisms remain unknown. Moreover, acute and prolonged EK may increase blood erythropoietin (EPO) concentrations in normoxia. Nonetheless, whether this effect is additive to hypoxia is unclear, as an EK-mediated attenuation of blood deoxygenation may counteract the [EPO] increase. In a randomized, placebo-controlled, crossover design, 13 male and two female participants completed four experimental sessions. Each included a high-intensity interval training session, followed by recovery either in normoxia or normobaric hypoxia (3000 m simulated altitude, $F_{I{O}_2}$ : 14.5%), supplemented with placebo or the commercial ketone precursor Ketone-IQ®. Macro- and microvascular function were assessed throughout a vascular occlusion protocol, using femoral artery blood flow and muscle oxygenation, respectively, after 2.5 and 5.5 h recovery. Additionally, serum EPO and endothelin-1 (ET-1) concentrations, and skeletal muscle expression of pro-angiogenic and vascular integrity markers were evaluated. In normoxia and hypoxia, EK increased post-occlusion blood velocity (+15%) and muscle reoxygenation rate (+9%). Furthermore, muscle expression of pro-angiogenic and vascular integrity markers (including vascular endothelial growth factor, peroxisome proliferator-activated receptor γ coactivator 1α, and angiopoietin-1) as well as serum [EPO] (+15%) increased with EK, while serum [ET-1] was reduced (-13%). EK appears as a promising strategy to enhance vascular function and integrity, angiogenic signalling, and circulating [EPO] in response to exercise and hypoxia, thereby facilitating beneficial adaptive responses. KEY POINTS: Exogenous ketosis (EK) enhances macro- and microvascular function during post-exercise recovery, in both normoxia and hypoxia, likely through reducing serum [ET-1]. Moreover, EK upregulates markers of exercise-induced angiogenesis and vascular integrity. Finally, an EK-related, post-exercise increase in serum [EPO] is additive to hypoxic exposure alone.