Impaired Autonomic Regulation of Resistance Arteries in Mice With Low Vascular Endothelial Growth Factor or Upon Vascular Endothelial Growth Factor Trap Delivery

Abstract

Background— Control of peripheral resistance arteries by autonomic nerves is essential for the regulation of blood flow. The signals responsible for the maintenance of vascular neuroeffector mechanisms in the adult, however, remain largely unknown. Methods and Results— Here, we report that VEGF ∂/∂ mice with low vascular endothelial growth factor (VEGF) levels suffer defects in the regulation of resistance arteries. These defects are due to dysfunction and structural remodeling of the neuroeffector junction, the equivalent of a synapse between autonomic nerve endings and vascular smooth muscle cells, and to an impaired contractile smooth muscle cell phenotype. Notably, short-term delivery of a VEGF inhibitor to healthy mice also resulted in functional and structural defects of neuroeffector junctions. Conclusions— These findings uncover a novel role for VEGF in the maintenance of arterial neuroeffector function and may help us better understand how VEGF inhibitors cause vascular regulation defects in cancer patients.

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond

“…On vascular smooth muscle cells, VEGF-A induces cell migration through the activation of VEGFR-2 79 and exerts a key function in the control of peripheral resistance arteries by autonomic nerves. 80 In the skeletal muscle, delivery of VEGF-A significantly improves the myogenic repair process following muscle injury via direct effects on both myogenic precursor cells and mature muscle fibers. 81,82 Of particular relevance, both VEGF-A and VEGF-B have been implied in the maintenance of physiological homeostasis in the heart, which depends strictly upon the interplay between different cell types.…”

Age-dependent expression of VEGFR2 in deep brain arteries in small vessel disease, CADASIL, and healthy brains

“…VEGFR2 has also been observed within VSMC, in small arteries of human spinal cord [6] and in blood vessels of peripheral tissues [8,36,37].…”

“…Our data do not support association with blood vessel density, or small vessel disease. Within experimental systems, the potent tyrosine kinase-linked VEGFR2 has functional effects on migration, differentiation state and functional phenotype of VSMC [7,8,22,36,37,43]. In human aortic VSMC cultures, and in adult mouse retina, VEGFR2 had a potent anti-migratory effect, mediated by VEGFR2-PDGFRβ receptor complexes [8].…”

“…In human aortic VSMC cultures, and in adult mouse retina, VEGFR2 had a potent anti-migratory effect, mediated by VEGFR2-PDGFRβ receptor complexes [8]. In transgenic mice (VEGF δ/δ ) lacking physiological levels of VEGF expression, arterial VSMC lacked mature contractile phenotype, and their sympathetic neuro-effector junctions were abnormal in structure and function [37]. VEGF δ/δ animals had greatly impaired cerebral blood flow autoregulation, in response to a hypoxic challenge (4-fold lower than wildtype mice) [37].…”

“…In transgenic mice (VEGF δ/δ ) lacking physiological levels of VEGF expression, arterial VSMC lacked mature contractile phenotype, and their sympathetic neuro-effector junctions were abnormal in structure and function [37]. VEGF δ/δ animals had greatly impaired cerebral blood flow autoregulation, in response to a hypoxic challenge (4-fold lower than wildtype mice) [37]. These data suggest that in adult brain arteries an adequate level of VEGF is required to maintain VSMC in a stable, non-migratory state, and in a fully-differentiated, contractile phenotype [8,37].…”