Proceedings of The Physiological Society

University College Dublin (2009) Proc Physiol Soc 15, SA59

Research Symposium

Endothelial ion channels and their role in arterial vasodilation

S. Brähler1, A. R. Kaistha1, V. J. Schmidt2, S. E. Woelfle2, C. Busch1, B. P. Kaistha1, J. P. Adelman3, H. Wulff4, J. Hoyer1, C. de Wit2, R. Köhler1

1. Nephrology, Biomedical Research Center, Philipps-University, Marburg, Germany. 2. Physiology, University Lübeck, Lübeck, Germany. 3. Neuroscience, Vollum Institute, Portland, Oregon, USA. 4. Pharmacology, UC Davis, Davis, California, USA.


The arterial endothelium critically contributes to blood pressure control by releasing vasodilating autacoids such as nitric oxide (NO), prostacyclin (PGI2), and the “endothelium-derived hyperpolarizing factor” (EDHF). The synthesis of these vasodilators requires Ca2+-mobilization which occurs in response to stimulation of G-protein coupled receptors or hemodynamic stimuli and involves Ca2+-release from the ER and/or Ca2+-influx. The latter is mediated by Ca2+-permeable cation channels. Also K+-channels are also important herein as their activity sets the membrane potential and/or produce hyperpolarization which provides the electrical driving force for Ca2+-influx and also initiates the EDHF-dilator response. In this overview we present recent insights from genetic animal models into the specific roles of the mechanosensitive Ca2+-permeable TRPV4 channel of the transient receptor potential gene family and of the Ca2+-activated K+-channels of small- and intermediate-conductance, (IK1 (KCa3.1) and SK3 (KCa2.3) in endothelial function and vasodilation. Pharmacological activation of endothelial TRPV4 channels by the selective 4alphaPDD causes a robust and strictly endothelium-dependent vasodilation mediated by NO and to lesser extent by EDHF. These dilations are absent in TRPV4-/- mice. While vasodilation in response to stimulation of G-protein coupled receptors (b y e.g. acetylcholine) is unaffected by the genetic deficiency, shear stress-induced vasodilation is eliminated in TRPV4-/- mice. Thus, shear stress-induced vasodilation critically depends on endothelial TRPV4 expression and identifies endothelial TRPV4 channels as molecular component in endothelial mechanotransduction. Endothelial KCa2.3 and KCa3.1 has been proposed to play a major role in EDHF-mediated dilation. To their precise roles in EDHF-response as well as in blood pressure control we generated mice deficient of both channels. Combined KCa3.1/KCa2.3 deficiency eliminates EDHF-type dilations in the conduit arteries and resistance sized arterioles. While KCa3.1 deficiency has a severe impact on acetylcholine-induced EDHF-type dilation, KCa2.3 deficiency impairs EDHF-type dilation to shear stress stimulation. Hence, KCa3.1/KCa2.3-deficient mice exhibit elevated blood pressure. Over-expression of KCa2.3 in KCa3.1-mice and pharmacological potentiation of KCa3.1 (by the novel KCa3.1-opener SKA-31) in KCa2.3-deficient KCa3.1-mice restors or augments, respectively, EDHF-type dilation and lower blood pressure. In conclusions, our findings in genetic animal models show that endothelial Ca2+-permaeble TRPV4 and hyperpolarizing KCa2.3 and KCa3.1 channels (with distinct stimulus-dependent functions) are fundamental determinants in endothelial functions and thus important effector proteins in the control of vascular tone. Therefore, pharmacological targeting of these ion channels may represent novel strategies for antihypertensive therapy and in cardiovascular disease states associated with endothelial dysfunction.

Where applicable, experiments conform with Society ethical requirements