VEGF-A inhibits agonist-mediated Ca²⁺ responses and activation of IK_Ca channels in mouse resistance artery endothelial cells

Key points: Prolonged exposure to vascular endothelial growth factor A (VEGF-A) inhibits agonist-mediated endothelial cell Ca²⁺ release and subsequent activation of intermediate conductance Ca²⁺-activated K⁺ (IK_Ca) channels, which underpins vasodilatation as a result of endothelium-dependent hyperpolarization (EDH) in mouse resistance arteries. Signalling via mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) downstream of VEGF-A was required to attenuate endothelial cell Ca²⁺ responses and the EDH-vasodilatation mediated by IK_Ca activation. VEGF-A exposure did not modify vasodilatation as a result of the direct activation of IK_Ca channels, nor the pattern of expression of inositol 1,4,5-trisphosphate receptor 1 within endothelial cells of resistance arteries. These results indicate a novel role for VEGF-A in resistance arteries and suggest a new avenue for investigation into the role of VEGF-A in cardiovascular diseases. Abstract: Vascular endothelial growth factor A (VEGF-A) is a potent permeability and angiogenic factor that is also associated with the remodelling of the microvasculature. Elevated VEGF-A levels are linked to a significant increase in the risk of cardiovascular dysfunction, although it is unclear how VEGF-A has a detrimental, disease-related effect. Small resistance arteries are central determinants of peripheral resistance and endothelium-dependent hyperpolarization (EDH) is the predominant mechanism by which these arteries vasodilate. Using isolated, pressurized resistance arteries, we demonstrate that VEGF-A acts via VEGF receptor-2 (R2) to inhibit both endothelial cell (EC) Ca²⁺ release and the associated EDH vasodilatation mediated by intermediate conductance Ca²⁺-activated K⁺ (IK_Ca) channels. Importantly, VEGF-A had no direct effect against IK_Ca channels. Instead, the inhibition was crucially reliant on the downstream activation of the mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 (MEK1/2). The distribution of EC inositol 1,4,5-trisphosphate (IP₃) receptor-1 (R1) was not affected by exposure to VEGF-A and we propose an inhibition of IP₃R1 through the MEK pathway, probably via ERK1/2. Inhibition of EC Ca²⁺ via VEGFR2 has profound implications for EDH-mediated dilatation of resistance arteries and could provide a mechanism by which elevated VEGF-A contributes towards cardiovascular dysfunction.