title: The cell motility modulator Slit2 is a potent inhibitor of platelet function.
abstract: BACKGROUND
  Vascular injury and atherothrombosis involve vessel infiltration by inflammatory leukocytes, migration of medial vascular smooth muscle cells to the intimal layer, and ultimately acute thrombosis. A strategy to simultaneously target these pathological processes has yet to be identified. The secreted protein, Slit2, and its transmembrane receptor, Robo-1, repel neuronal migration in the developing central nervous system. More recently, it has been appreciated that Slit2 impairs chemotaxis of leukocytes and vascular smooth muscle cells toward diverse inflammatory attractants. The effects of Slit2 on platelet function and thrombus formation have never been explored.
  
  
  RESULTS
  We detected Robo-1 expression in human and murine platelets and megakaryocytes and confirmed its presence via immunofluorescence microscopy and flow cytometry. In both static and shear microfluidic assays, Slit2 impaired platelet adhesion and spreading on diverse extracellular matrix substrates by suppressing activation of Akt. Slit2 also prevented platelet activation on exposure to ADP. In in vivo studies, Slit2 prolonged bleeding times in murine tail bleeding assays. Using intravital microscopy, we found that after mesenteric arteriolar and carotid artery injury, Slit2 delayed vessel occlusion time and prevented the stable formation of occlusive arteriolar thrombi.
  
  
  CONCLUSIONS
  These data demonstrate that Slit2 is a powerful negative regulator of platelet function and thrombus formation. The ability to simultaneously block multiple events in vascular injury may allow Slit2 to effectively prevent and treat thrombotic disorders such as myocardial infarction and stroke.
authors.affiliation: The Hospital for Sick Children, 555 University Ave, Toronto, ON, Canada M5G 1X8.
authors.forename: Sajedabanu
authors.initials: S
authors.lastname: Patel
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Huang
authors.forename: Adili
authors.initials: A
authors.lastname: Reheman
authors.forename: Fred G
authors.initials: FG
authors.lastname: Pluthero
authors.forename: Swasti
authors.initials: S
authors.lastname: Chaturvedi
authors.forename: Ilya M
authors.initials: IM
authors.lastname: Mukovozov
authors.forename: Soumitra
authors.initials: S
authors.lastname: Tole
authors.forename: Guang-Ying
authors.initials: GY
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Yves
authors.initials: Y
authors.lastname: Durocher
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni
authors.forename: Walter H A
authors.initials: WH
authors.lastname: Kahr
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Robinson
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002712:Chlorides / Q000009:adverse effects; D005290:Ferric Compounds / Q000009:adverse effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000494:pharmacology / Q000502:physiology*; D010973:Platelet Adhesiveness / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D012307:Risk Factors; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C024555:ferric chloride