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

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) Ca release and the associated EDH vasodilatation mediated by intermediate conductance Ca -activated K (IK ) channels. Importantly, VEGF-A had no direct effect against IK 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 (IP ) receptor-1 (R1) was not affected by exposure to VEGF-A and we propose an inhibition of IP R1 through the MEK pathway, probably via ERK1/2. Inhibition of EC Ca 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.

Endothelial Ca2+ Signaling, Angiogenesis and Vasculogenesis: Just What It Takes to Make a Blood Vessel

“…However, it remains to be elucidated whether VEGF actually recruits IK Ca channels and, vice versa, whether IK Ca channels sustain VEGF-induced extracellular Ca 2+ influx during the angiogenic activity. It should, however, be pointed out that VEGF inhibits InsP 3 -dependent ER Ca 2+ mobilization and the Ca 2+ -dependent recruitment of IK Ca channels in mouse pressurized resistance arteries [191].…”

Comparison of Adrenergic and Purinergic Receptor Contributions to Vasomotor Responses in Mesenteric Arteries of C57BL/6J Mice and Wistar Rats

“…Isolated mesenteric arteries have been used historically [38] and continue to be used for microcirculation studies [9, 19, 22, 23, 39] due to their important role in regulating blood flow to the small and large intestine, in large part through adrenergic signaling. While NE, a neurotransmitter released from sympathetic nerves might be a more physiological agonist because it acts on both α 1 and α 2 AR; we focused initially on PE, an α 1 AR agonist, for 3 reasons.…”

“…Male C57BL/6J mice (30–35 g, 11–16-week old) and male Wistar rats (225–250 g) were euthanized, following Schedule 1 procedures of the UK Animals (Scientific Procedures) Act 1986 [19, 23]. The mesentery was excised and pinned radially in a glass petri dish containing +4°C MOPS buffer containing (mmol/L): 145 NaCl, 4.7 KCl, 2.0 CaCl 2 , 1.17 MgSO 4 7H 2 O, 2.0 MOPS, 1.2 NaH 2 PO 4 , 5.0 glucose, 2.0 pyruvate, 0.02 EDTA, and 2.75 NaOH (pH 7.40 ± 0.02).…”

The Role of the VEGF Family in Coronary Heart Disease

“…The depressed channel promoted vasodilation through endothelial-dependent hyperpolarization (EDH) of the resistance artery in mice. VEGF-A downstream of MEK signaling weakened the above vasodilation response of ECs, indicating that VEGF-A played a new role in the resistance artery and provided a novel aspect of treating cardiovascular disease with VEGF-A ( 53 ).…”