Mechanosensation and the basis of myogenic tone development

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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: