Connexins and Vascular Tone

Gap junctions contribute to regulation of vascular tone. Thus, pharmacologic agents and connexin mimetic peptides, which inhibit gap junctional communication, also inhibit vasodilation. In fact, the well-documented phenomenon of conducted vasodilatation in conduit arteries is explained by longitudinal NO conduction along the vascular wall through gap junctions. Further, connexin-mimetic peptides inhibit the transmission of endothelial hyperpolarization to underlying smooth muscle cells, consistent with a role for heterologous endothelial-vascular smooth muscle communicating junctions in so-called endothelium-derived hyperpolarizing factor (EDHF)-induced vasodilation [8]. EDHF-type vessel relaxation mediated by gap-junctional communication is more prominent for small than large vessels. This is consistent with the finding that functional gap-junctional communication is present in small vessels as indicated by the presence of Ca2+ waves that propagate between endothelial cells [9].

Consistent with the prominent expression of Cx40 by endothelial cells, endothelial electrical conduction, vasodi-lation, and smooth muscle activation are defective in Cx40-deficient mice. These mice also have increased blood pressure, indicating a predominant role for Cx40, rather than Cx43, in establishing gap junctional connections between vascular smooth muscle and endothelium [10].

The neonatal lethal phenotype of Cx43-deficient mice has hampered the understanding of Cx43 in vascular function. To address this, Liao et al. [11] used cre expression driven by the Tie 2 promoter to preferentially excise the Cx43 gene from endothelial cells. These mice develop normally and their endothelial cells express two other con-nexins, Cx37 and Cx40, but they have abnormally low blood pressure and a lowered heart rate. Lowered blood pressure was due to increased plasma NO production, which was most likely due to increased eNOS activity. However, since endothelial NO production is linked to gap-junctional coupling between vascular smooth muscle and endothelial cells, this indicates that Cx43 depletion actually enhanced coupling between these cells, perhaps through enhanced formation of homomeric Cx40 gap junction channels.

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