Implications of Electrical Communication in Brain Blood Flow Regulation and Stroke Injury

Abstract

An integrated network of cerebral arteries actively coordinates brain blood flow in accordance with metabolic demands. Large regional changes require synchronised vasomotor responses across vessel segments starting at the origin of a stimulus and spreading to the major upstream resistors. The coordination of vasomotor tone is intimately tied to the spread of charge through gap junctions, a process that equalizes membrane potential, [Ca2+] and myosin light chain phosphorylation among thousands of smooth muscle cells. Coordinated responses are critically important during cerebrovascular accidents (i.e. stroke) where the synchronized dilation of collateral vessels diverts flow into ischemic tissue. We hypothesized that electrical communication, via gap junctions, plays a central role and that dysfunctional communication between vascular cells impairs collateral responses, increasing stroke injury. Using isolated cerebral arteries from mouse, hamster and resected human tissue, we show that electrical stimuli can effectively spread along vascular cells in an endothelium dependant manner. Genetic deletion of Connexin40 (Cx40−/−), a component protein of gap junctions, compromised electrical communication in the cerebral arteries. Subjecting Cx40−/− mice to focal cerebral ischemia induced greater deficit in cerebral blood flow than in wild type controls, during stroke and the subsequent reperfusion period. This attenuation of blood flow translated to augmented stroke injury in the Cx40−/− mice. In closing, our study illustrates the presence of robust electrical communication and that compromising this integrated process restricts the ability of the cerebral circulation to respond to, and moderate injury from vascular accidents, including stroke.Support or Funding InformationThis work is supported by an operating grant to Dr Welsh from the Natural Science and Engineering Council of Canada (NSERC). Dr Welsh is the Roraback Chair in Neuroscience and Vascular Biology at the University of Western Ontario. A. Zechariah is supported by Canadian Institutes of Health Research (CIHR) Postdoctoral scholarship, Alberta Innovates Postdoctoral scholarship and Eyes High Postdoctoral fellowship. Dr. Tuor is supported by a grant from CIHR.