Characterization of the Role of Integrin alpha 5 beta 1 in Platelet Function, Hemostasis, and Experimental Thrombosis

Objective Integrins are key regulators of various platelet functions. The pathophysiological importance of most platelet integrins has been investigated, with the exception of alpha 5 beta 1, a receptor for fibronectin. The aim of this study was to characterize the role of alpha 5 beta 1 in megakaryopoiesis, platelet function, and to determine its importance in hemostasis and arterial thrombosis. Approach and Results We generated a mouse strain deficient for integrin alpha 5 beta 1 on megakaryocytes and platelets (PF4Cre-alpha 5(-/-)). PF4Cre- alpha 5(-/-) mice were viable, fertile, and presented no apparent signs of abnormality. Megakaryopoiesis appears unaltered as evidence by a normal megakaryocyte morphology and development, which is in agreement with a normal platelet count. Expression of the main platelet receptors and the response of PF4Cre-alpha 5(-/-) platelets to a series of agonists were all completely normal. Adhesion and aggregation of PF4Cre-a5(-/-) platelets under shear flow on fibrinogen, laminin, or von Willebrand factor were unimpaired. In contrast, PF4Crea5(-/-) platelets displayed a marked decrease in adhesion, activation, and aggregation on fibrillar cellular fibronectin and collagen. PF4Cre-a5(-/-) mice presented no defect in a tail-bleeding time assay and no increase in inflammatory bleeding in a reverse passive Arthus model and a lipopolysaccharide pulmonary inflammation model. Finally, no defects were observed in three distinct experimental models of arterial thrombosis based on ferric chloride-induced injury of the carotid artery, mechanical injury of the abdominal aorta, or laser-induced injury of mesenteric vessels. Conclusion In summary, this study shows that platelet integrin alpha 5 beta 1 is a key receptor for fibrillar cellular fibronectin but is dispensable in hemostasis and arterial thrombosis. Role of alpha 5 beta 1 in Hemostasis and Thrombosis Janus-Bell et al.