Solving the Enigma of Myoendothelial Feedback

The study examined whether second messenger flux through myoendothelial gap junctions initiates a feedback response that attenuates arterial constriction. It was specifically hypothesized that when agonists elicit depolarization and a rise in second messenger concentration, Ca 2+ / IP 3 flux across the myoendothelial gap junctions is sufficient to drive discrete endothelial Ca 2+ transients that activate downstream Ca 2+ ‐sensitive targets which attenuate but do not abolish constriction. In support of this general hypothesis, initial functional observations revealed that contractile/electrical responsiveness of hamster retractor muscle feed arteries to superfused phenylephrine was enhanced by intermediate conductance (IK) Ca 2+ ‐activated K + inhibitors and agents that limited Ca 2+ mobilization within the endoplasmic reticulum. Endothelial Ca 2+ imaging secondarily showed that phenylephrine elicited recruitable Ca 2+ wavelets, discrete endothelial events driven by IP 3 receptor activation and whose characteristics were distinct from Ca 2+ pulsars. Electron microscopy along with immunohistochemistry confirmed that endothelial projections make contact with smooth muscle and that IP 3 receptors and IK channels are discretely expressed near the endothelial nucleus where projections are typically observed. Computational modeling subsequently revealed the importance of myoendothelial IP 3 but not Ca 2+ flux in driving the endothelial response, a finding confirmed by direct experimentation. From these findings, we conclude that discrete endothelial Ca 2+ events induced by myoendothelial IP 3 flux do indeed activate Ca 2+ sensitive ion channels to elicit an electrical feedback response that moderates vascular contractility.