Vascular Endothelial Growth Factor Inhibitor-Induced Hypertension: From Pathophysiology to Prevention and Treatment Based on Long-Acting Nitric Oxide Donors

Abstract

Hypertension is the most common adverse effect of the inhibitors of vascular endothelial growth factor (VEGF) pathway-based therapy (VEGF pathway inhibitors therapy, VPI therapy) in cancer patients. VPI includes monoclonal antibodies against VEGF, tyrosine kinase inhibitors, VEGF Traps, and so-called aptamers that may become clinically relevant in the future. All of these substances inhibit the VEGF pathway, which in turn causes a decrease in nitric oxide (NO) and an increase in blood pressure, with the consequent development of hypertension and its final events (e.g., myocardial infarction or stroke). To our knowledge, there is no current study on how to provide an optimal therapy for patients on VPI therapy with hypertension. This review summarizes the roles of VEGF and NO in vessel biology, provides an overview of VPI agents, and suggests a potential treatment procedure for patients with VPI-induced hypertension.

Cardiovascular toxic effects of targeted cancer therapy

“…VEGF inhibitors induce an imbalance between vasodilation and vasoconstriction; as a consequence, they increase the peripheral vascular resistance and blood pressure (31,37,38).…”

“…VEGF also leads to the production of another vasodilator, prostacyclin I2 (PGI2), and decreases endothelin-1 (ET-1) level, a potent vasoconstrictor. Thus, VEGF inhibitors decrease the vascular tone, leading to hypertension (31,37,38).…”

“…VEGF is an important mediatorof endothelial cell proliferation and survival. Therefore, the inhibition of VEGF signaling would cause vascular rarefaction and endothelial cell apoptosis (38).…”

VEGF Pathway Inhibitors–Induced Hypertension: Next Step in Therapy

“…4 The incidence of high-grade hypertension in patients receiving bevacizumab ranged between 2.4% and 14.8%. 5,6 High-grade hypertension is associated with a significant increase in morbidity and may subsequently result in dose reduction or discontinuation of VPI therapy. Although the mechanism underlying the development of hypertension induced by ngiogenesis inhibition still remains to be elucidated, decreased nitric oxide (NO) bioavailability is thought to be a critical factor.…”

“…Although the mechanism underlying the development of hypertension induced by ngiogenesis inhibition still remains to be elucidated, decreased nitric oxide (NO) bioavailability is thought to be a critical factor. Kruzliak and colleagues 3,5 described the existence of two major pathophysiological mechanisms resulting in hypertension induced by VPI: (1) direct inhibition of NO production with reduced vasodilatation and increased vasoconstriction; and (2) NO deficiency-mediated increase in vascular medial cells proliferation, leading to the fixation of hypertension. Considering these two mechanisms, they suggest that administration of NO donors in VPI-treated patients will prevent the occurrence of hypertension and its associated complications.…”