Angiogenic Doping: Plausible Yet Difficult to Detect

In endurance athletes, cardiovascular oxygen delivery is the primary limitation to performance. While the focus of athletes and regulatory bodies has been on hemoglobin and red blood cells, the increased oxygen-delivering capacity resulting from training is also a consequence of the expanded blood volume, which requires vascular adaptation. Angiogenesis-the formation of new blood vessels from pre-existing ones-is an understudied area in exercise physiology due to the need for invasive procedures. Among the vascular endothelial growth factors, VEGF-A and VEGF-D are the most potent angiogenic inducers and thus candidates for doping purposes. VEGF expression can be stimulated by several external factors, of which oxygen deprivation and its mimics are the most significant in the context of doping. A controlled overexpression of VEGF-A or VEGF-D, and the resulting blood vessel formation, could directly increase vascular space and indirectly increase blood volume and athletic ability. A master regulatory gene such as HIF-1α would be a preferred target over any single growth factor, as it would affect red blood cell production and vascular expansion synchronously. Currently available compounds may already be misused, with potential unintended consequences, including the aggravation of inflammatory diseases or tumor progression. Due to the ease of implementation and difficulty of detection, angiogenic doping and possible detection strategies deserve to be studied further.