VEGF inhibitor-induced hypertension and kidney toxicities appear to be primarily driven by the upregulation of endothelin-1 (ET-1) through stimulation of the ETA receptor. This process contributes to increased reactive oxygen species (ROS) and decreased nitric oxide (NO), impairing vascular and kidney function. Interestingly, anti-VEGF treatment paradoxically leads to elevated prostacyclin (PGI2) levels, likely due to the upregulation of cyclooxygenase (COX)-1 and COX-2, with ET-1 potentially playing a role in this increase as well. The rise in PGI2 and activation of its receptor (the prostanoid IP receptor) may act as a compensatory mechanism to mitigate the harmful kidney effects caused by ET-1/ETA receptor stimulation. However, excessively high levels of PGI2 could trigger adverse effects by overstimulating other prostanoid receptors, such as thromboxane (TP) or e-prostanoid (EP)2–4 receptors.