Connexin40 (Cx40) is a crucial component in gap junctions (GJ) with a strong impact on cardiovascular and renal physiology since Cx40-deficient mice exhibit pronounced hypertension, altered negative feedback of renin secretion causing an increased plasma renin activity, and impaired conduction of endothelium-dependent dilations. Cx40 is expressed abundantly in endothelial and renin-producing cells and we assessed the effects of cell-specific Cx40 deletion. Expectedly, lack of Cx40 in renin-producing cells led to hypertension that was renin-dependent since low-salt diet and blockade of angiotensin-converting enzyme abrogated the enhanced arterial pressure. In contrast, deletion of Cx40 in endothelial cells did not elevate arterial pressure but strongly reduced the conduction of endothelium-dependent dilations in the microcirculation similar to global Cx40-deficient mice. Such attenuation was not present in hypertensive mice being deficient for Cx40 in renin-producing cells. Thus, a vascular and a renal phenotype can be well distinguished. Notably, the expression of the second connexin that is found abundantly in endothelial cells (Cx37) is strongly reduced in conducting arteries and lacking in arterioles in global Cx40-deficient hypertensive mice. This altered expression of Cx37 is not related to the hypertension, but solely due to the lack of Cx40 because it was also observed in normotensive endothelial-cell specific but not in hypertensive renin-producing cell specific Cx40-deficient mice. These findings raise the question if the defect in the conduction of dilatory signals along arterioles is indeed related to the lack of Cx40 or if the combined deletion of Cx40 and Cx37 is required to produce this effect. Hitherto, we studied animals carrying a mutated non-conducting Cx40 identified in humans (Ala96->Ser, A96S). In these animals, the conduction of endothelium-dependent dilation is similarly impaired despite the fact that the non-conducting mutated Cx40 as well as Cx37 was identified in endothelial cell membranes in arterioles by immunohistochemistry. This suggests that Cx37 cannot support the conduction of dilatory signals in arterioles in the absence of a functional Cx40. Moreover, animals carrying this mutated Cx40 were also hypertensive suggesting similar mechanisms with regard to Cx40 function in renin-producing cells. Thus, we conclude that Cx40 is the most important connexin in cardiovascular and kidney physiology.