Nitric oxide reduces electrical coupling in microvascular endothelial cells by targeting connexin 37

Abstract

Increased nitric oxide (NO) production in septic mice impairs arteriolar conducted vasoconstriction, involving a cGMP-independent pathway. We recently reported that Cx37 null mice have impaired conducted vasoconstriction. Therefore, arteriolar Cx37 may be a potential target for NO signaling in sepsis. We examined the effect of NO on electrical coupling in monolayers of cultured microvascular endothelial cells derived from the hindlimb skeletal muscle of wild-type (WT), Cx37 null, Cx40 null and Cx43G60S (nonfunctional mutant) mice. To assess coupling, we measured the spread of electrical current injected into the monolayer and calculated the monolayer intercellular resistance (inverse measure of coupling). The NO donor DETA (500 μg/ml, 3 h) significantly reduced coupling (i.e. increased resistance) in cells from WT, Cx40 null and Cx43G60S mice, but not in cells from Cx37 null mice. In WT cells, a 5–10 min application of DETA reduced coupling, indicating that NO affects rapid signaling and/or Cx37 function. Since electrical coupling along the arteriolar endothelium is critical in arteriolar conduction, we propose that NO in sepsis impairs arteriolar conducted vasoconstriction by targeting Cx37.