Conclusions

While the ABP has significantly curbed traditional blood doping and erythropoietin misuse, the evolving landscape of performance enhancement now faces the formidable challenge of next-generation doping. Angiogenic doping might be an attractive use case for athletes aiming to implement next-generation doping, particularly through the manipulation of VEGF signaling via HIF-1α, prolyl hydroxylases, or protein tyrosine phosphatases. Perhaps we are failing already to detect some of the cutting-edge angiogenic doping techniques. For example, PTP inhibitors are not routinely checked by WADA, and targeted small-molecule drugs could easily fall below the detection threshold. If this is the case, the true prevalence of doping among top athletes might be much higher than typically assumed [362].

Enhancing oxygen delivery, a critical determinant of endurance performance, can be achieved not only by altering blood composition but also by increasing vascularization through angiogenesis. The observed interplay among hypoxia-inducible factors, prolyl hydroxylases, and emerging agents such as targeted hypoxia mimetics suggests ample potential for illicit manipulation. In contrast, achieving functional and beneficial angiogenesis by direct application of angiogenic factors such as VEGF-A or VEGF-D is complex, requiring precise control of growth factor gradients and isoform-specific effects, which are not easily achievable in the context of doping at this time.

The pursuit of angiogenic doping carries significant and unpredictable health risks, including the potential for triggering tumor progression and the exacerbation of various non-malignant diseases. In the long run, the detection of angiogenic gene doping or editing poses formidable challenges, given the possible orthotopic expression of endogenous proteins, the limitations of current non-invasive imaging technologies for the skeletal muscle microvasculature, and the improvements of advanced gene-editing techniques such as CRISPR.

If history is any guide, athletes will experiment with pro-angiogenic drugs and regimens in the hope of gaining a performance advantage—even before the FDA approves such agents. Some of these substances are already accessible, while others, such as gene doping and gene editing, still face significant technical challenges before becoming practical for doping purposes. Angiogenic doping, along with its potential long-term physiological consequences and the difficulties of detection, warrants dedicated research to safeguard both the integrity of competitive sport and the health of athletes.