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 December 2, 2019; First 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 5

Femoral artery ligation results in loss of the venous perivalvular transcriptional and antithrombotic phenotypes.

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Femoral artery ligation results in loss of the venous perivalvular trans...
Immunostaining of mouse saphenous veins was performed 72 hours after femoral artery ligation (FAL) to reduce venous flow, and relative quantitation of protein levels in luminal (L), valvular (V), and sinus (S) endothelial cells was measured. (A and B) Loss of perivalvular endothelial expression of the FOXC2 (n = 5 control, n = 6 FAL valves) and PROX1 (n = 7 control, n = 12 FAL valves) transcription factors following FAL. (C–E) Loss of perivalvular endothelial expression of the antithrombotic proteins THBD (n = 9 control, FAL valves), EPCR (n = 9 control, n = 8 FAL valves), and TFPI (n = 7 control, n = 9 FAL valves) following FAL. (F) Gain of perivalvular endothelial expression of the prothrombotic protein vWF following FAL (n = 6 control, n = 8 FAL valves). White dashed lines indicate luminal venous endothelial cells, and green dotted lines indicate perivalvular endothelial cells. For all graphs the mean is represented by the bar with each dot representing a replicate, and error bars indicate SD. Significance was determined by a 2-tailed Mann-Whitney test. *P < 0.05.