A tiny electrical signal spreading across the inner lining of a blood vessel can tell the surrounding muscle to relax, lowering blood pressure—and this process is failing in cardiovascular disease. This research tackles a fundamental gap in knowledge: how endothelial cells, which line all blood vessels, use calcium sparks and potassium channels to generate a hyperpolarising signal that travels to the smooth muscle and widens the artery. The mechanism is independent of nitric oxide and prostacyclin, two better-known pathways, and is disrupted by the endothelial dysfunction seen in hypertension and atherosclerosis. The team has already identified that two specific potassium channels (KCa2.3 and KCa3.1) are confined to the endothelium and cluster at points of contact with smooth muscle, forming a signalling microdomain. They now need to understand how this circuit is controlled by pressure, muscle activity, and hormones like angiotensin and thromboxane. This is fundamental science. It will not produce a drug or device tomorrow. But a clearer wiring diagram of how arteries dilate could eventually reveal new targets for treating high blood pressure, stroke, and vascular dementia—conditions where current therapies still leave many patients poorly controlled.
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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.
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