Hui Sonya, Levy Andrew S, Slack Daniel L, Burnstein Marcus J, Errett Lee, Bonneau Daniel, Latter David, Rotstein Ori D, Bolz Steffen-Sebastian, Lidington Darcy, Voigtlaender-Bolz Julia
Toronto Centre for Microvascular Medicine, University of Toronto and St. Michael's Hospital, Toronto, Canada; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada.
Department of Physiology, University of Toronto, Toronto, Canada.
PLoS One. 2015 Sep 14;10(9):e0138142. doi: 10.1371/journal.pone.0138142. eCollection 2015.
We recently identified sphingosine-1-phosphate (S1P) signaling and the cystic fibrosis transmembrane conductance regulator (CFTR) as prominent regulators of myogenic responsiveness in rodent resistance arteries. However, since rodent models frequently exhibit limitations with respect to human applicability, translation is necessary to validate the relevance of this signaling network for clinical application. We therefore investigated the significance of these regulatory elements in human mesenteric and skeletal muscle resistance arteries. Mesenteric and skeletal muscle resistance arteries were isolated from patient tissue specimens collected during colonic or cardiac bypass surgery. Pressure myography assessments confirmed endothelial integrity, as well as stable phenylephrine and myogenic responses. Both human mesenteric and skeletal muscle resistance arteries (i) express critical S1P signaling elements, (ii) constrict in response to S1P and (iii) lose myogenic responsiveness following S1P receptor antagonism (JTE013). However, while human mesenteric arteries express CFTR, human skeletal muscle resistance arteries do not express detectable levels of CFTR protein. Consequently, modulating CFTR activity enhances myogenic responsiveness only in human mesenteric resistance arteries. We conclude that human mesenteric and skeletal muscle resistance arteries are a reliable and consistent model for translational studies. We demonstrate that the core elements of an S1P-dependent signaling network translate to human mesenteric resistance arteries. Clear species and vascular bed variations are evident, reinforcing the critical need for further translational study.
我们最近发现，鞘氨醇-1-磷酸（S1P）信号传导和囊性纤维化跨膜传导调节因子（CFTR）是啮齿动物阻力动脉肌源性反应的重要调节因子。然而，由于啮齿动物模型在人类适用性方面常常存在局限性，因此有必要进行转化研究以验证该信号网络在临床应用中的相关性。因此，我们研究了这些调节元件在人肠系膜和骨骼肌阻力动脉中的重要性。从结肠或心脏搭桥手术期间收集的患者组织标本中分离出肠系膜和骨骼肌阻力动脉。压力肌动描记法评估证实了内皮完整性以及稳定的去氧肾上腺素和肌源性反应。人肠系膜和骨骼肌阻力动脉均（i）表达关键的S1P信号元件，（ii）对S1P作出收缩反应，并且（iii）在S1P受体拮抗作用（JTE013）后丧失肌源性反应。然而，虽然人肠系膜动脉表达CFTR，但人骨骼肌阻力动脉不表达可检测水平的CFTR蛋白。因此，调节CFTR活性仅能增强人肠系膜阻力动脉的肌源性反应。我们得出结论，人肠系膜和骨骼肌阻力动脉是转化研究的可靠且一致的模型。我们证明，S1P依赖性信号网络的核心元件可转化到人肠系膜阻力动脉。明显的物种和血管床差异很明显，这进一步凸显了进行转化研究的迫切需求。
