Signalling circuitry controlling hyperpolarization and dilatation in resistance arteries. (360G-Wellcome-089815_Z_09_Z)

In arteries, endothelial cells continually suppress blood pressure by hyperpolarizing smooth muscle. This represents a primary and fundamental physiological control mechanism independent of NO/prostacylin, modulated by autacoids and disrupted by the endothelial dysfunction caused by cardiovascular disease. We discovered hyperpolarization follows KCa-channel (KCa2.3 and 3.1) activation, and that these channels are restricted to the endothelium and are differentially activated depending on vas omotor tone. Focal expression of these KCa-channels on endothelial projections towards adjacent smooth muscle form an integral part of a unique signalling microdomain. At this site, Ca2+ signals from activated smooth muscle first arrive and potentially activate these endothelial KCa-channels. Together, they represent a heterocellular signalling circuit subject to control by a host of signalling intermediates. Using small mesenteric, cerebral, and cremaster arteries at physiological pressures, we will investigate how radial and axial spread of hyperpolarization integrates diameter change in these differentially regulated vascular beds. Techniques including live-cell imaging and electrophysiological recording will reveal how endothelial cell Ca2+-events originate and link to KCa-hyperpolarization, how alignment of membrane effectors shapes the hyperpolarization controlling diameter, how signalling is modified by intraluminal pressure and muscle stimulation and how physiological agonis ts like thromboxane, angiotensin and adrenaline alter KCa-channel activity, expression, distribution and thus dilatation.