Reply to letter by McIntyre et al.

The comments by McIntyre et al.1 are interesting and certainly provide insights into additional mechanisms whereby inhibitors of the vascular endothelial growth factor (VEGF)/ VEGF receptor system impact cardiovascular disease. With respect to hypertension, experimental and clinical evidence indicates that the blood pressureeelevating effect of VEGF inhibitors (VEGFIs) is rapid, occurring within 1-2 days after starting treatment. This suggests that physiological processes regulating acute blood pressure responses are activated. From a vascular viewpoint, such phenomena involve acute vasodilation and reduced vasomotor tone, processes regulated primarily by activation of endothelial nitric oxide synthase and release of nitric oxide (NO), a potent vasodilator. In addition, activation of the sympathetic nervous system plays a fundamental role in acute changes in blood pressure. Although there is extensive experimental evidence demonstrating a role for NO in VEGFI-mediated hypertension, less is known about the role of the nervous system. However, there is some indication that activation or dysregulation of the nervous system by VEGF inhibition may impact blood pressure regulation, with studies showing impaired autonomic regulation of resistance arteries in mice with low levels of VEGF.2 Some studies have also shown that VEGFIs are neurotoxic and as such could influence neural control of blood pressure.3 However, other studies failed to demonstrate any significant effect of VEGFIs on the sympathetic nervous system, because plasma catecholamine levels were unchanged in sunitinibtreated mice with severe hypertension.4 The prospective pilot study by McIntyre et al.1 is certainly timely and should shed light on a potential relationship between bevacizumab and autonomic nervous system function in humans. Thepreliminary data,1 although certainly interesting, unfortunately do not reveal anything about the effects on blood pressure. It would be important to know whether heart rate changes observed in the McIntyre et al. study parallel blood pressure responses. Hopefully, future studies by these researchers will address this important aspect so that a better understanding of the putative role of the autonomic system in VEGFI-induced hypertension can be unraveled.