title: Monocyte-endothelial adhesion is modulated by Cx43-stimulated ATP release from monocytes.
abstract: Adhesion of circulating monocytes to vascular endothelial cells is a crucial event in development of vascular inflammatory conditions, including atherosclerosis. We investigated the roles of connexin43 (Cx43) and ATP release on monocyte-endothelial adhesion. Cx43 function and expression were manipulated by connexin channel inhibitors, overexpression and siRNA. Connexin channel inhibitors rapidly decreased ATP release from U937 monocytes and increased adhesion to human umbilical vein endothelial cells (HUVEC). Monocyte ATP release correlated with Cx43 expression, not with Cx37 expression. Exogenous adenosine (ADO) or ATP decreased adhesion, and inhibition of ATP conversion to ADO increased adhesion. We infer that monocyte Cx43 channel activity causes ATP release, likely via Cx43-containing hemichannels, and that ATP decreases adhesion via conversion to ADO. Inhibition of HUVEC connexin channel activity did not affect ATP release or adhesion. In contrast, expression of Cx43 protein in U937 cells enhanced adhesion. Thus, Cx43 channel function and expression have opposite effects: Cx43 channel function in monocytes, but not in HUVEC, rapidly decreases adhesion via ATP release and conversion to ADO, whereas Cx43 expression itself enhances adhesion. These studies suggest that local regulation of monocyte Cx43 activity within the vasculature can dynamically modulate the monocyte-endothelial adhesion that is an initiating event in vascular inflammatory pathologies, with the baseline adhesion set by Cx43 expression levels. This balance of rapid and tonic influences may be crucial in development of vascular pathologies.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, PR China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Yuan
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Dengpan
authors.initials: D
authors.lastname: Wu
authors.forename: Meiling
authors.initials: M
authors.lastname: Yu
authors.forename: Suzhi
authors.initials: S
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Tao
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014657:Vasculitis / Q000378:metabolism
chemical_list: D018031:Connexin 43; D000255:Adenosine Triphosphate; D000241:Adenosine