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. METHODS AND 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.
journal_name
Circulationjournal_title
Circulationauthors
Patel S,Huang YW,Reheman A,Pluthero FG,Chaturvedi S,Mukovozov IM,Tole S,Liu GY,Li L,Durocher Y,Ni H,Kahr WH,Robinson LAdoi
10.1161/CIRCULATIONAHA.112.105452subject
Has Abstractpub_date
2012-09-11 00:00:00pages
1385-95issue
11eissn
0009-7322issn
1524-4539pii
CIRCULATIONAHA.112.105452journal_volume
126pub_type
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