Regulation of Endothelial Cell Procoagulant Activity by TMEM16 Scramblases


Alec A. Schmaier, M.D., Ph.D.
Beth Israel Deaconess Medical Center, Harvard Medical School
Boston, U.S.

Procoagulant endothelial cell (EC) dysfunction is a hallmark of cardiovascular disease. To promote blood coagulation, phosphatidylserine (PS) must be rapidly externalized to the outer leaflet of the cell membrane. PS is the major acidic phospholipid in human membranes, constituting 2% to 20% of the total phospholipid mass of adult human plasma and intracellular membranes. Activated platelets are thought to provide the majority of procoagulant PS, whose externalization is regulated by the phospholipid scramblase transmembrane protein 16F (TMEM16F). This was one of the goals of the research presented by Alec Schmaier, M.D., Ph.D., of Beth Israel Deaconess Medical Center/Harvard Medical School on Sunday, July 18, 2021.  As it is unknown whether endothelial-derived PS contributes to hemostasis and thrombosis and what regulates its externalization, Schmaier commented that the identification of regulators of PS scrambling in ECs and the determination of their contribution of vessel wall–derived PS to thrombosis in vivo were key goals.

Via immunofluorescence microscopy, flow cytometry, and assessment of PS externalization during thrombus formation, Schmaier commented that two TMEM16 family members, TMEM16F and TMEM16E, both were required for tenase and prothrombinase activity on ECs. Cells deficient in TMEM16E or TMEM16F displayed reduced PS scrambling in response to TNFα or calcium ionophore but expressed normal levels of tissue factor. Additionally, the majority of PS externalization was derived from the vessel wall, not platelets, noted Schmaier. These findings support the overall conclusion that the EC is regulated by TMEM16F and TMEM16E. TMEM16 inhibition may reduce the prothrombotic potential of the vessel wall.


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