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

Journal article

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+ (IKCa) channels. Importantly, VEGF‐A had no direct effect against IKCa 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.

Authors: Ye, X; Beckett, T; Bagher, P; Garland, C; Dora, K

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Journal of Physiology
• Volume: 596
• Issue: 16
• Pages: 3553-3566
• Publication date: 2018-06-03
• Acceptance date: 2018-05-15
• DOI: 10.1113/JP275793
• ISSN: 0022-3751
• Keywords: endothelium‐derived hyperpolarizing factor; endothelial cell calcium; MEK; VEGF‐A; vasodilation