Shear stress-induced atherosclerotic plaque composition in ApoE(-/-) mice is modulated by connexin37.
OBJECTIVE
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. 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.


METHODS
Shear 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.


RESULTS
Plaque 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.


CONCLUSIONS
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. Hence, local hemodynamic factors may modify the risk for adverse atherosclerotic disease outcomes associated to a polymorphism in the human Cx37 gene.
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Department of Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland.
A
A
Pfenniger
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Department of Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland.
M J
MJ
Meens
Department of Bioengineering, Imperial College, London, UK.
R M
RM
Pedrigi
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Department of Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland.
B
B
Foglia
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Department of Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland.
E
E
Sutter
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Department of Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland.
G
G
Pelli
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Department of Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland.
V
V
Rochemont
Department of Oncology, CHUV and University of Lausanne, Epalinges, Switzerland.
T V
TV
Petrova
Department of Bioengineering, Imperial College, London, UK.
R
R
Krams
Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Department of Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland. Electronic address: Brenda.KwakChanson@unige.ch.
B R
BR
Kwak
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D017209:Apoptosis; D050197:Atherosclerosis; D002448:Cell Adhesion; D002454:Cell Differentiation; D002784:Cholesterol / Q000737:chemistry; D017630:Connexins / Q000235:genetics* / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D006439:Hemodynamics; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D009991:Oscillometry; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D033081:Shear Strength; D000097006:Gap Junction alpha-4 Protein
D000255:Adenosine Triphosphate; D001057:Apolipoproteins E; D002784:Cholesterol; D017630:Connexins; D000097006:Gap Junction alpha-4 Protein
Atherosclerosis; Connexin; Macrophages; Plaque stability