Which Connexins Connect

See related article, pages 1292–1299 Electrical signaling via gap junctions modulates vascular function via 2 physiologically interrelated mechanisms, namely dilations/constrictions that propagate longitudinally along the vessel wall,1–4 and the EDHF phenomenon, in which relaxation is facilitated by the transmission of endothelial hyperpolarization to smooth muscle via a radial myoendothelial pathway.5 Gap junctions are composed from 2 hemichannels, each constructed from 6 connexin (Cx) protein subunits, whose alignment across the extracellular space permits intercellular diffusion of ions and small molecules <1 kDa in size and confers electrical continuity. Coupling is enhanced by the clustering of up to several hundred individual gap junction channels to form plaques that can be visualized by immunostaining at points of cell–cell contact. Vascular cells variably express 4 connexin subtypes (Cxs 37, 40, 43, and 45) with protein expression generally being more abundant in the endothelium than in smooth muscle cells. Most commonly, endothelial plaques contain Cx37 and Cx40 and medial plaques contain Cx43. This distribution is seen, for example, in the rabbit iliac artery in which synthetic peptides selectively targeted against Cx37 and Cx40 attenuate endothelium-dependent subintimal smooth muscle hyperpolarization, whereas peptides targeted against Cx43 attenuate the spread of medial hyperpolarization.6 In muscular arteries electrical signaling pathways thus appear to correlate closely with immunostaining findings. In this issue of Circulation Research Wolfle and colleagues1 have analyzed longitudinal conduction in mice with replacement of Cx40 by “knock in” of Cx45 (denoted as Cx40KI45 mice). Responses were initiated by localized application of the endothelium-dependent dilators acetylcholine (ACh) and bradykinin (BK) to cremasteric arterioles in wild-type (WT), Cx40 knockout (Cx40KO), and Cx40KI45 animals, and diameter changes were monitored dynamically by intravital microscopy. Responses were found to propagate for more than 1 mm within 1 sec in WT mice without significant decay, whereas remote dilation …