Endothelial cell-specific knockout of connexin 43 causes hypotension and bradycardia in mice

Connexin 43 (Cx43) is a protein expressed in a variety of mammalian tissues . However, the lack of specific blockers and the absence of known genetic m utants have hampered the investigation of the function of this protein. Cx4 3-null mice die shortly after birth, thus preventing functional studies in vivo. Here, we report the generation and characterization of a vascular end othelial cell-specific deletion of the Cx43 gene (VEC Cx43 KO) in mice by u sing the loxP/Cre system. Using homologous recombination, a mouse line was created carrying loxP sites flanking exon 2 of the Cx43 gene ("floxed" mice ). To produce cell specific deletion of the Cx43 gene, these mice were cros sed with animals from a line carrying the Tie 2-Cre transgene. The homozygo us VEC Cx43 KO mice survived to maturity. However, they were hypotensive an d bradycardic when compared with heterozygous VEC Cx43 KO mice, or to the f loxed Cx43 gene mice. The hypotension was associated with marked elevation of plasma nitric oxide (NO) levels as well as elevated plasma angiotensin ( Ang) 1 and 11. We hypothesize that endothelial cell Cx43 plays a key role i n the formation and/or action of NO, and that the elevation of Ang 11 is a secondary event. The specific cellular basis for the hypotension remains to be established, but our findings support the idea that endothelial Cx43 ga p junctions are involved in maintaining normal vascular function; moreover, these animals provide the opportunity to determine more clearly the role o f endothelial Cx43 in vascular development and homeostasis.