Hemodynamic regulation of perivalvular endothelial gene expression prevents deep venous thrombosis
John D. Welsh, … , Juan M. Jimenez, Mark L. Kahn
John D. Welsh, … , Juan M. Jimenez, Mark L. Kahn
Published November 11, 2019
Citation Information: J Clin Invest. 2019;129(12):5489-5500. https://doi.org/10.1172/JCI124791.
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Research Article Vascular biology

Hemodynamic regulation of perivalvular endothelial gene expression prevents deep venous thrombosis

Abstract

Deep venous thrombosis (DVT) and secondary pulmonary embolism cause approximately 100,000 deaths per year in the United States. Physical immobility is the most significant risk factor for DVT, but a molecular and cellular basis for this link has not been defined. We found that the endothelial cells surrounding the venous valve, where DVTs originate, express high levels of FOXC2 and PROX1, transcription factors known to be activated by oscillatory shear stress. The perivalvular venous endothelial cells exhibited a powerful antithrombotic phenotype characterized by low levels of the prothrombotic proteins vWF, P-selectin, and ICAM1 and high levels of the antithrombotic proteins thrombomodulin (THBD), endothelial protein C receptor (EPCR), and tissue factor pathway inhibitor (TFPI). The perivalvular antithrombotic phenotype was lost following genetic deletion of FOXC2 or femoral artery ligation to reduce venous flow in mice, and at the site of origin of human DVT associated with fatal pulmonary embolism. Oscillatory blood flow was detected at perivalvular sites in human veins following muscular activity, but not in the immobile state or after activation of an intermittent compression device designed to prevent DVT. These findings support a mechanism of DVT pathogenesis in which loss of muscular activity results in loss of oscillatory shear–dependent transcriptional and antithrombotic phenotypes in perivalvular venous endothelial cells, and suggest that prevention of DVT and pulmonary embolism may be improved by mechanical devices specifically designed to restore perivalvular oscillatory flow.

Authors

John D. Welsh, Mark H. Hoofnagle, Sharika Bamezai, Michael Oxendine, Lillian Lim, Joshua D. Hall, Jisheng Yang, Susan Schultz, James Douglas Engel, Tsutomu Kume, Guillermo Oliver, Juan M. Jimenez, Mark L. Kahn

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Figure 7

Human DVT arises in association with loss of the perivalvular endothelial transcription factor and antithrombotic phenotypes.

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Human DVT arises in association with loss of the perivalvular endothelia...
(A and B) Model of the relationship between muscular activity, perivalvular oscillatory flow, perivalvular endothelial cell gene expression, and venous thrombosis. In the active state, muscular activity stimulates oscillatory flow in the venous valve sinus, driving endothelial expression of the shear-regulated FOXC2 and PROX1 transcription factors. Shear-regulated transcription factor activity upregulates expression of the antithrombotic proteins THBD, EPCR, and TFPI while simultaneously downregulating expression of the prothrombotic proteins vWF, P-selectin, and ICAM1 to maintain a highly antithrombotic environment (A). Inactivity and lack of muscular contraction results in perivalvular endothelial loss of expression of the shear-regulated transcription factors, loss of THBD, EPCR, and TFPI expression, and gain of vWF, P-selectin, and ICAM1 expression, resulting in thrombin generation and formation of DVT (B). (C–E) Human DVT is associated with loss of endothelial expression of FOXC2 and PROX1 in the valve sinus. (C) After death due to pulmonary embolism, femoral vein samples containing the valve at the anastomosis of the superficial and deep femoral veins were harvested from a leg without DVT (top) and from the contralateral leg with DVT in situ (bottom). (D–F) Immunostaining for FOXC2 and PROX1 were performed on sections from the valves shown in C. Arrowheads indicate FOXC2+ and PROX1+ nuclei in E and F. (G–J) DVT is associated with endothelial gain of expression of the prothrombotic protein vWF and loss of the antithrombotic proteins THBD, EPCR, and TFPI in the valve sinus. The white dashed line indicates the endothelial layer. VL, luminal face of the valve; VS, sinus face of the valve; S, vessel wall in the valve sinus.