Mechanosensation and the basis of myogenic tone development

在动态条件下，动脉张力受到多种刺激的调节，包括神经元活动、组织代谢和血管内压。一个世纪前，贝利斯首次推测动脉可以对血压的变化做出反应。这种“肌源性反应”可在多种血管床上观察到，并依赖于平滑肌[Ca~(2+)]升高。压力升高可通过以下两种途径增加平滑肌细胞内钙离子浓度：1)通过动脉去极化驱动的钙通道活性；2)肌浆网(SR)内钙释放。虽然过去的研究已经弄清楚了哪些离子通道和离子储存库参与了这一过程，但关于平滑肌细胞实际上是如何“感觉”血管内压力以促进胞浆[Ca~(2+)]升高的问题仍然存在。为了与这个关键问题保持一致，NSERC的这项建议将解决黏附复合蛋白及其下游信号通路是否使平滑肌细胞能够感知机械力并提高胞浆[Ca~(2+)]。在接下来的5年里，申请者将考察以下角色：

Under dynamic conditions, arterial tone is regulated by multiple stimuli including neuronal activity, tissue metabolism and intravascular pressure. A century ago, Bayliss first surmised that arteries could respond to changes in blood pressure. The "myogenic response" is observable in a variety of vascular beds and is dependent upon a rise in smooth muscle [Ca2+]. Elevated pressure augments smooth muscle [Ca2+] by augmenting: 1) Ca2+ channel activity through a mechanism driven by arterial depolarization; and 2) internal Ca2+ release from the sarcoplasmic reticulum (SR). While past studies have clarified which ion channels and stores participate, questions remains as to how smooth muscle cells actually "sense" intravascular pressure to facilitate the cytosolic [Ca2+] rise. In keeping with this key question, this NSERC proposal will address whether adhesion complex proteins and their downstream signaling pathways enable smooth muscle cells to sense mechanical forces and elevate cytosolic [Ca2+]. Over the next 5 years, the applicant will examine the role of: