Red blood cell-derived semaphorin 7A accelerates carotid arterial thrombosis under disturbed flow via interacting with platelet αIIbβ3.

BACKGROUND

Red blood cells (RBCs) play an important role in thrombosis, yet the molecular mechanisms by which they contribute to thrombus formation remain incompletely defined. Semaphorin 7A (Sema7A) is highly expressed on RBCs as a John Milton Hagen antigen, but its functional contribution to arterial thrombosis has not been fully elucidated.

OBJECTIVES

To define the contribution of RBC-derived Sema7A to arterial thrombosis under disturbed blood flow.

METHODS

An arterial thrombosis model was established by combining partial carotid ligation with FeCl3-induced injury. Mice with global or erythrocyte-specific deletion of Sema7A were generated. Thrombus formation was assessed by histological and flow chamber analyses. Mass spectrometry and coimmunoprecipitation were performed to identify Sema7A-binding partners in platelets.

RESULTS

Our arterial thrombus model exhibited increased RBC recruitments in thrombosis. Global deletion of Sema7A markedly reduced thrombus size and RBC- and platelet-rich areas and impaired platelet and RBC adhesion on collagen. Mice lacking Sema7A specifically in RBCs exhibited smaller thrombi and delayed vessel occlusion compared with wild-type controls. Recombinant human Sema7A enhanced platelet activation and adhesion in the presence of agonists, whereas antibody blockade of Sema7A attenuated RBC and platelet recruitment. Mechanistically, Sema7A interacted with platelet integrin αIIb, promoting the recruitment of Talin1 and Lims1 and facilitating integrin-dependent signaling.

CONCLUSION

RBC-derived Sema7A plays a key role in promoting thrombosis under disturbed flow. Targeting the Sema7A-integrin αIIb axis may provide a potential therapeutic approach for arterial thrombotic disorders.