Pericytes are vascular mural cells that contract and relax in response to vasoactive stimuli to regulate neurovascular coupling and cerebral blood flow. Pericytes are damaged and degenerate in Alzheimer's disease (AD). We previously showed that the level of the regulatory vasoconstrictor, endothelin-1 (EDN1), is elevated in AD cerebral cortex and upregulated by amyloid-beta (Aβ). We have used electrical impedance analysis to monitor the contractile and proliferative response of cultured human fetal and adult brain-derived pericytes to EDN1 in real-time. EDN1 caused transient, dose-dependent contraction of fetal and adult brain pericytes that was mediated by EDN1 type A receptors and increased the subsequent proliferation of fetal but not adult cells. The contractile responses to EDN1 were weaker in the adult pericytes. The EDN1-mediated contractile response of fetal pericytes was unchanged after exposure to Aβ1 - 40 or Aβ1 - 42 (0.1-10 μM) for 1 h but both contraction and subsequent relaxation were significantly impaired upon exposure to Aβ for 24 h. These data suggest that chronic exposure to Aβ interferes with EDN1-mediated pericyte contractility, potentially contributing to neurovascular uncoupling and reduced cerebral blood flow in AD.

中文翻译：

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对 Endothelin-1 和 Aβ 肽的周细胞收缩反应：通过电阻抗测定法评估。

周细胞是血管壁细胞，可响应血管活性刺激而收缩和放松，以调节神经血管耦合和脑血流。周细胞在阿尔茨海默病 (AD) 中受损和退化。我们之前表明，调节性血管收缩剂内皮素-1 (EDN1) 的水平在 AD 大脑皮层中升高，并被淀粉样蛋白-β (Aβ) 上调。我们使用电阻抗分析实时监测培养的人类胎儿和成人脑源性周细胞对 EDN1 的收缩和增殖反应。EDN1 引起由 EDN1 A 型受体介导的胎儿和成人脑周细胞的短暂、剂量依赖性收缩，并增加随后的胎儿而非成人细胞的增殖。成年周细胞对 EDN1 的收缩反应较弱。在暴露于 Aβ1-40 或 Aβ1-42 (0.1-10 μM) 1 小时后，EDN1 介导的胎儿周细胞收缩反应没有改变，但在暴露于 Aβ 24 小时后，收缩和随后的松弛均显着受损。这些数据表明，长期暴露于 Aβ 会干扰 EDN1 介导的周细胞收缩力，可能导致 AD 中神经血管解偶联和脑血流量减少。