Distinct Endothelium-Derived Hyperpolarizing Factors Emerge In Vitro and In Vivo and Are Mediated in Part via Connexin 40–Dependent Myoendothelial Coupling

The endothelium-derived hyperpolarizing factor (EDHF) contributes critically to the regulation of vascular tone. Its dependency on direct signaling through myoendothelial gap junctions composed of connexins (Cx) is controversially discussed. We studied the impact of Cx40 in EDHF-type dilations in vivo and in vitro (wire and pressure myography) in small arteries (A. gracilis) using different Cx40-deficient mouse models. Acetylcholine induced prominent EDHF-type dilations (inhibition of NO synthase and cyclooxygenase) of ≈90% (maximum effect) in wild-type and Cx40-deficient vessels (Cx40 −/− ) in vitro under isobaric conditions. In contrast, under isometric conditions, EDHF-type relaxations were nearly abrogated in Cx40 −/− (9±3%) but only slightly reduced in wild-type vessels (45±4%; P fl :TIE2-Cre: 17±3%; Cx40-floxed controls: 67±6%; P