Location, Location, Location: Juxtaposed calcium-signaling microdomains as a novel model of the vascular smooth muscle myogenic response

Small arteries and arterioles constrict in response to increases in intraluminal pressure through a process called “myogenic tone” or the “myogenic response” (McCarron et al., 1989). Development of myogenic tone has profound physiological implications; it contributes substantially to regulation of systemic blood pressure, maintenance of capillary/tissue perfusion, and auto­ regulation of blood flow to specific organs, such as kid­ neys and brain (Davis, 2012). Thus, understanding the mechanisms that govern the myogenic response is ger­ mane to our understanding of the cardiovascular sys­ tem as a whole. The current thinking is that myogenic tone is regulated by a “push/pull” relationship between vasoconstrictor and vasodilator mechanisms, both of which are regulated through focal increases in intra­ cellular Ca concentration within cellular microdomains (Hill­Eubanks et al., 2011). The interaction and prox­ imity of these two vasoregulatory pathways are critical to the regulation of myogenic tone and proper vascular function. However, even with the breadth and extent of investigation into the myogenic response, a definitive model of the structure, localization, and composition of these cellular­signaling domains remains elusive. Karlin (2015) describes a new model of an arterial smooth muscle cell that, unlike previous models (Bennett et al., 2005; Kapela et al., 2008), incorporates five inter­ connected Ca compartments and 37 separate protein components into two distinct microdomains. When tested, the proposed model accurately recapitulated the changes in membrane potential and intracellular Ca observed experimentally in response to increases in intraluminal pressure. Moreover, when used to simu­ late pressure­independent responses to vasoconstrictors (ATP, ­adrenergic agonists) and vasodilators (nitric oxide, epoxyeicosatrienoic acids, ­adrenergic agonists), this model continued to accurately represent the changes in smooth muscle cell membrane potential and intracellular Ca recorded experimentally under the same conditions.