title: Connexin 37 limits thrombus propensity by downregulating platelet reactivity.
abstract: BACKGROUND
  Formation of platelet plug initiates hemostasis after vascular injury and triggers thrombosis in ischemic disease. However, the mechanisms leading to the formation of a stable thrombus are poorly understood. Connexins comprise a family of proteins that form gap junctions enabling intercellular coordination of tissue activity, a process termed gap junctional intercellular communication.
  
  
  RESULTS
  In the present study, we show that megakaryocytes and platelets express connexin 37 (Cx37). Deletion of the Cx37 gene in mice shortens bleeding time and increases thrombus propensity. Aggregation is increased in murine Cx37(-/-) platelets or in murine Cx37(+/+) and human platelets treated with gap junction blockers. Intracellular microinjection of neurobiotin, a Cx37-permeant tracer, revealed gap junctional intercellular communication in platelet aggregates, which was impaired in Cx37(-/-) platelets and in human platelets exposed to gap junction blockers. Finally, healthy subjects homozygous for Cx37-1019C, a prognostic marker for atherosclerosis, display increased platelet responses compared with subjects carrying the Cx37-1019T allele. Expression of these polymorphic channels in communication-deficient cells revealed a decreased permeability of Cx37-1019C channels for neurobiotin.
  
  
  CONCLUSIONS
  We propose that the establishment of gap junctional communication between Cx37-expressing platelets provides a mechanism to limit thrombus propensity. To our knowledge, these data provide the first evidence incriminating gap junctions in the pathogenesis of thrombosis.
authors.affiliation: Service and Central Laboratory of Hematology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, rue du Bugnon 46, CH-1011 Lausanne, Switzerland. anne.angelillo-scherrer@chuv.ch
authors.forename: Anne
authors.initials: A
authors.lastname: Angelillo-Scherrer
authors.forename: Pierre
authors.initials: P
authors.lastname: Fontana
authors.forename: Laurent
authors.initials: L
authors.lastname: Burnier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Roth
authors.forename: Rocco
authors.initials: R
authors.lastname: Sugamele
authors.forename: Anne
authors.initials: A
authors.lastname: Brisset
authors.forename: Sandrine
authors.initials: S
authors.lastname: Morel
authors.forename: Séverine
authors.initials: S
authors.lastname: Nolli
authors.forename: Esther
authors.initials: E
authors.lastname: Sutter
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chassot
authors.forename: Claude
authors.initials: C
authors.lastname: Capron
authors.forename: Delphine
authors.initials: D
authors.lastname: Borgel
authors.forename: François
authors.initials: F
authors.lastname: Saller
authors.forename: Marc
authors.initials: M
authors.lastname: Chanson
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Kwak
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D001760:Bleeding Time; D001792:Blood Platelets / Q000502:physiology*; D017630:Connexins / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D017629:Gap Junctions / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010974:Platelet Aggregation / Q000502:physiology; D011110:Polymorphism, Genetic / Q000502:physiology; D013927:Thrombosis / Q000235:genetics* / Q000503:physiopathology*; D055815:Young Adult; D000097006:Gap Junction alpha-4 Protein
chemical_list: D001710:Biotin; D017630:Connexins; D000097006:Gap Junction alpha-4 Protein; C070614:neurobiotin