Vascular Cardio-Oncology: Vascular Endothelial Growth Factor inhibitors and hypertension

Since the formation of new blood vessels is essential for tumour growth and metastatic spread, inhibition of angiogenesis by targeting the vascular endothelial growth factor (VEGF) pathway is an effective strategy for various types of cancer, most importantly renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. However, VEGF inhibitors have serious side effects, most importantly hypertension and nephropathy. In case of fulminant hypertension, this may only be handled by lowering the dosage since the blood pressure rise is proportional to the amount of VEGF inhibition. These effects pathophysiologically and clinically resemble the most severe complication of pregnancy, preeclampsia, in which case an insufficient placenta leads to a rise in sFlt-1 levels causing a decrease in VEGF availability. Due to this overlap, studies in preeclampsia may provide important information for VEGF inhibitor-induced toxicity and vice versa. In both VEGF inhibitor-induced toxicity and preeclampsia, endothelin (ET)-1 appears to be a pivotal player. In this review, after briefly summarizing the anticancer effects, we discuss the mechanisms that potentially underlie the unwanted effects of VEGF inhibitors, focusing on ET-1, nitric oxide and oxidative stress, the reninangiotensinaldosterone system, and rarefaction. Given the salt sensitivity of this phenomenon, as well as the beneficial effects of aspirin in preeclampsia and cancer, we next provide novel treatment options for VEGF inhibitor-induced toxicity, including salt restriction, ET receptor blockade, and cyclo-oxygenase inhibition, in addition to classical antihypertensive and renoprotective drugs. We conclude with the recommendation of therapeutic drug monitoring to improve patient outcome.