A reduced LVEF has been observed during treatment with sunitinib in up to of patients, and in up to of patients treated with bevacizumab. Some patients treated with sunitinib had a decline in LVEF of more than, but no clinical signs or symptoms of congestive heart failure were observed.For bevacizumab, congestive heart failure has been observed in up to of patients with breast cancer, but this is probably related to previous chemotherapy. Blood pressure is regulated by cardiac output, blood volume regulation through the kidney, baroreceptors and the vasculature itself through the release of hormones such as endothelin. The first indications that VEGF was important for blood pressure regulation came from preclinical studies in which animals were infused with VEGF.In these in vivo experiments a clear drop in blood pressure after VEGF administration was observed. In a clinical trial in which VEGF was used to treat ischaemia, a drop of systolic blood pressure of was observed.The diastolic P E R S P E C T I V E S blood pressure was also decreased but to a lesser extent.Endothelial cells promote vasodilation by http://inhibit09.online/archives/59 secreting NO and PGI. VEGF is known to induce the release of these factors by endothelial cells.Downstream of the VEGF receptor on endothelial cells, the PIK signalling cascades are responsible for eNOS induction and NO production.Blocking VEGFR signalling will therefore decrease the production of these vasodilators, leading to vascular resistance and increased blood pressure.Independent of vasodilator release, VEGF can induce hypotension through an endothelial baroreceptor response.Upon infusion with VEGF, the baroreceptor signalling cascade was decreased in rats, thereby decreasing blood pressure.In the case of VEGF inhibition, one might expect the opposite disturbance increased signalling with increased blood pressure.The exact interaction of VEGF and the baroreceptors is unknown.The normal blood pressure regulation determined by the interplay of vascular cells, smooth muscle cells and baroreceptor regulation is shown.Baroreceptors are located in the carotid arteries in the neck and send signals to the brain and subsequently to the vasomotor centre.If these receptors are stretched too much by high blood pressure they reduce their activating signals to the vasomotor centre, whereas in the caseof lowblood pressure they act ivate the vasomotor centre. Hypertension in response to angiogenesis inhibitors might not only be induced by the lack of vasodilatory effects, but may also be due to an inappropriate reduction in the density of capillaries and arterioles, which may induce peripheral vascular resistance resulting in hypertension.In addition, hypertension might be caused by an increase in vascular stiffness.Blockade of VEGF signalling may also http://inhibit09.online/archives/51 disturb the balance between VEGF and endothelin.Endothelin is a potent endogenous vasoconstrictor, and its expression is correlated with that of VEGF.The exact role of their interaction is unknown, but one may expect that they function to keep the blood pressure tightly in balance. NATURE REV IEWS C A N C E R VO LUM E J U N E P E R S P E C T I V E S arteries and arterioles as a consequence of inhibiting new vessel formation.