Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
Department of Pharmaceutics, University of Washington, Seattle, WA, USA.
Physiol Rep. 2020 Mar;8(5):e14395. doi: 10.14814/phy2.14395.
Equilibrative nucleoside transporter 4 (ENT4), encoded by SLC29A4, mediates the flux of both 5-hydroxytryptamine (5-HT) and adenosine across cell membranes. We hypothesized that loss of ENT4 function in mice would modify the effects of these established regulators of vascular function. Male and female wild-type (WT) and slc29a4-null (ENT4-KO) mice were compared with respect to their hemodynamics and mesenteric vascular function. Male ENT4-KO mice had a complete loss of myogenic tone in their mesenteric resistance arteries. This was accompanied by a decrease in blood flow in the superior mesenteric artery in the male ENT4-KO mice, and a reduced responsiveness to 5-HT. In contrast, endothelium-dependent relaxations of mesenteric arteries from female ENT4-KO mice were more sensitive to Ca -activated K (K ) channel blockade than WT mice. Female ENT4-KO mice also demonstrated an enhanced vasodilatory response to adenosine in vivo that was not seen in males. Ketanserin (5-HT inhibitor) and GR55562 (5-HT inhibitor) decreased 5-HT-induced tone, but only ketanserin inhibited the relaxant effect of 5-HT in mesenteric arteries. 5-HT-evoked increases in tone were elevated in arteries from ENT4-KO mice upon block of endothelial relaxant pathways, with arteries from female ENT4-KO mice showing the greatest increase. Adenosine A receptor expression was decreased, while other adenosine transporter subtypes, as well as adenosine deaminase and adenosine kinase were increased in mesenteric arteries from male, but not female, ENT4-KO mice. These findings indicate that deletion of slc29a4 leads to sex-specific changes in vascular function with significant consequences for regulation of blood flow and pressure by adenosine and 5-HT.
平衡核苷转运蛋白 4（ENT4）由 SLC29A4 编码，介导 5-羟色胺（5-HT）和腺苷穿过细胞膜的通量。我们假设在小鼠中丧失 ENT4 功能会改变这些已确立的血管功能调节剂的作用。雄性和雌性野生型（WT）和 slc29a4 敲除（ENT4-KO）小鼠在血流动力学和肠系膜血管功能方面进行了比较。雄性 ENT4-KO 小鼠的肠系膜阻力动脉的肌源性张力完全丧失。这伴随着雄性 ENT4-KO 小鼠的肠系膜上动脉血流量减少，以及对 5-HT 的反应性降低。相比之下，雌性 ENT4-KO 小鼠肠系膜动脉的内皮依赖性舒张对 Ca 激活的 K（K）通道阻断剂的敏感性高于 WT 小鼠。雌性 ENT4-KO 小鼠还表现出对腺苷的体内血管舒张反应增强，而雄性小鼠则没有这种反应。酮色林（5-HT 抑制剂）和 GR55562（5-HT 抑制剂）降低了 5-HT 诱导的张力，但只有酮色林抑制了肠系膜动脉中 5-HT 的舒张作用。在阻断内皮舒张途径后，ENT4-KO 小鼠的动脉中 5-HT 引起的张力增加，而雌性 ENT4-KO 小鼠的动脉则显示出最大的增加。腺苷 A 受体表达减少，而其他腺苷转运体亚型以及腺苷脱氨酶和腺苷激酶在雄性，但不是雌性，ENT4-KO 小鼠的肠系膜动脉中增加。这些发现表明，slc29a4 的缺失导致血管功能的性别特异性变化，对腺苷和 5-HT 调节血流和血压有重大影响。
