Recent Advances in Hypertension and Cardiovascular Toxicities With Vascular Endothelial Growth Factor Inhibition

Abstract

Physiologically, vascular endothelial growth factors (VEGF) and their receptors (VEGFR) play a critical role in vascular development, neogenesis, angiogenesis, endothelial function and vascular tone. Pathologically, VEGF-VEGFR signaling induces dysregulated angiogenesis, which contributes to the growth and spread of tumors. The development of VEGF-VEGFR inhibitors (VEGFIs) has thus proven to be a valuable strategy in the management of a number of malignancies, yielding improved survival outcomes. Not surprisingly, VEGFIs are now standard of care as first-line monotherapy for some cancers and the scope of this class of drugs is growing. However with the promise of improved outcomes, VEGFIs also led to clinically relevant toxicities, especially hypertension and cardiovascular disease (CVD). As such, cancer patients treated with VEGFIs may have improved cancer outcomes, but at the cost of an increased risk of CVD. Indeed, dose intensity and protracted use of these drugs can be limited by cardiovascular side effects and patients may require dose reduction or drug withdrawal, thus compromising anti-cancer efficacy and survival. Here we summarize the vascular biology of VEGF-VEGFR signaling and discuss the cardiovascular consequences and clinical impact of VEGFIs. New insights into molecular mechanisms whereby VEGFIs cause hypertension and heart disease are highlighted.

Figure 1

Diagram demonstrating signalling pathways induced by VEGFR activation. VEGFR is activated by VEGF binding and by non-ligand mechansims (shear stress, stretch). Both genomic and non-genomic pathways are stimulated leading to endothelial cell growth, differentiation, migration, adhesion and vasodilation. p, phosphorylation site of VEGFR tyrosine kinase; eNOS, endothelial nitric oxide synthase; NO, nitric oxide.

Figure 2

Schematic illustrating possible pathophysiological processes whereby VEGF-VEGFR inhibition contributes to the development of hypertension and preeclampsia. Four major classes of VEGF-VEGFR inhibitors, including monoclonal VEGF antibodies, anti-VEGFR2 antibodies, soluble decoy receptors (VEGF-traps) and small molecule VEGFR tyrosine kinase inhibitors (TKI) are used clinically as anti-angiogenesis drugs in cancer. In pregnancy, placenta-derived soluble fms-like tyrosine kinase 1 (s-Flt), acts as a VEGF-trap reducing free VEGF availability for binding to VEGFR2R. These processes result in reduced VEGFR signaling and consequent reduction in production of vasodilators (NO and PGI₂), increased production of vasoconstrictors (ET-1), oxidative stress and rarefaction, resulting in increased vascular tone and arterial remodeling. Reduced pressure natriuresis and impaired lymphatic function contribute to volume overload. p, phosphorylation site of tyrosine kinase; ROS, reactive oxygen species; NO, nitric oxide; ET-1, endothelin-1; Ab, antibody; ECF, extracellular fluid; CVD, cardiovascular disease, PGI2, prostaglandin I2