Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.
School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
J Physiol. 2018 Aug;596(16):3553-3566. doi: 10.1113/JP275793. Epub 2018 Jul 2.
Prolonged exposure to vascular endothelial growth factor A (VEGF-A) inhibits agonist-mediated endothelial cell Ca release and subsequent activation of intermediate conductance Ca -activated K (IK ) 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 Ca responses and the EDH-vasodilatation mediated by IK activation. VEGF-A exposure did not modify vasodilatation as a result of the direct activation of IK 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.
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.
血管内皮生长因子 A（VEGF-A）的长时间暴露会抑制激动剂介导的内皮细胞 Ca 释放，以及随后的中间电导 Ca 激活的 K（IK）通道的激活，这是由于内皮细胞依赖性超极化（EDH）导致的小鼠阻力动脉血管舒张的基础。VEGF-A 下游的丝裂原激活蛋白/细胞外信号调节激酶激酶（MEK）信号传导对于减轻内皮细胞 Ca 反应和 IK 激活介导的 EDH 血管舒张是必需的。VEGF-A 的暴露并没有改变 IK 通道的直接激活所导致的血管舒张，也没有改变内皮细胞中肌醇 1,4,5-三磷酸受体 1 的表达模式。这些结果表明 VEGF-A 在阻力动脉中具有新的作用，并为研究 VEGF-A 在心血管疾病中的作用提供了新的途径。
血管内皮生长因子 A（VEGF-A）是一种有效的通透性和血管生成因子，也与微血管重塑有关。VEGF-A 水平的升高与心血管功能障碍的风险显著增加有关，尽管尚不清楚 VEGF-A 如何产生有害的、与疾病相关的影响。小阻力动脉是外周阻力的主要决定因素，内皮细胞依赖性超极化（EDH）是这些动脉血管舒张的主要机制。本研究使用分离的加压阻力动脉，证明 VEGF-A 通过血管内皮生长因子受体 2（R2）作用，抑制内皮细胞（EC）Ca 释放和中间电导 Ca 激活的 K（IK）通道介导的相关 EDH 血管舒张。重要的是，VEGF-A 对 IK 通道没有直接作用。相反，这种抑制主要依赖于丝裂原激活蛋白/细胞外信号调节激酶激酶 1/2（MEK1/2）的下游激活。EC 肌醇 1,4,5-三磷酸（IP）受体 1（R1）的分布不受 VEGF-A 的影响，我们提出通过 MEK 途径抑制 IP R1，可能通过 ERK1/2。VEGFR2 对 EC Ca 的抑制对 EDH 介导的阻力动脉舒张有深远的影响，并可能为升高的 VEGF-A 导致心血管功能障碍提供一种机制。
