Shear stress-induced atherosclerotic plaque composition in ApoE−/− mice is modulated by connexin37

•Shear stress patterns influence atherogenesis and plaque stability; low laminar shear stress (LLSS) promotes unstable plaques whereas oscillatory shear stress (OSS) induces more stable plaques.•The gap junction protein Cx37 is atheroprotective by inhibiting ATP-dependent monocyte adhesion.•A genetic polymorphism in the human Cx37 gene (GJA4) has been frequently reported as a potential prognostic marker for atherosclerosis. However, not all studies had the same outcome.•Flow-driven modulation of atherosclerotic lesions is affected by Cx37.•Cx37 deletion increased the size of atherosclerotic lesions in OSS regions and abrogated the development of a stable plaque phenotype under OSS in ApoE−/− mice.•It is thus conceivable that local hemodynamic factors may modify the risk for adverse atherosclerotic disease outcomes associated to the genetic polymorphism in the human Cx37 gene.

ObjectiveShear stress patterns influence atherogenesis and plaque stability; low laminar shear stress (LLSS) promotes unstable plaques whereas oscillatory shear stress (OSS) induces more stable plaques. Endothelial connexin37 (Cx37) expression is also regulated by shear stress, which may contribute to localization of atherosclerotic disease. Moreover, Cx37 reduces initiation of atherosclerosis by inhibiting monocyte adhesion. The present work investigates the effect of Cx37 on the phenotype of plaques induced by LLSS or OSS.MethodsShear stress-modifying casts were placed around the common carotid artery of ApoE−/− or ApoE−/−Cx37−/− mice, and animals were placed on a high-cholesterol diet for 6 or 9 weeks. Atherosclerotic plaque size and composition were assessed by immunohistochemistry.ResultsPlaque size in response to OSS was increased in ApoE−/−Cx37−/− mice compared to ApoE−/− animals. Most plaques contained high lipid and macrophage content and a low amount of collagen. In ApoE−/− mice, macrophages were more prominent in LLSS than OSS plaques. This difference was reversed in ApoE−/−Cx37−/− animals, with a predominance of macrophages in OSS plaques. The increase in macrophage content in ApoE−/−Cx37−/− OSS plaques was mainly due to increased accumulation of M1 and Mox macrophage subtypes. Cx37 expression in macrophages did not affect their proliferation or their polarization in vitro.ConclusionCx37 deletion increased the size of atherosclerotic lesions in OSS regions and abrogated the development of a stable plaque phenotype under OSS in ApoE−/− mice. Hence, local hemodynamic factors may modify the risk for adverse atherosclerotic disease outcomes associated to a polymorphism in the human Cx37 gene.