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Proline-rich tyrosine kinase Pyk2 regulates deep vein thrombosis

Deep vein thrombosis results from the cooperative action of leukocytes, platelets, and endothelial cells. The proline-rich tyrosine kinase Pyk2 regulates platelet activation and supports arterial thrombosis. In this study, we combined pharmacological and genetic approaches to unravel the role of Pyk...

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Autores principales: Momi, Stefania, Canino, Jessica, Vismara, Mauro, Galgano, Luca, Falcinelli, Emanuela, Guglielmini, Giuseppe, Taranta, Giulia Ciarrocca, Guidetti, Gianni Francesco, Gresele, Paolo, Torti, Mauro, Canobbio, Ilaria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9152972/
https://www.ncbi.nlm.nih.gov/pubmed/35142150
http://dx.doi.org/10.3324/haematol.2021.279703
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author Momi, Stefania
Canino, Jessica
Vismara, Mauro
Galgano, Luca
Falcinelli, Emanuela
Guglielmini, Giuseppe
Taranta, Giulia Ciarrocca
Guidetti, Gianni Francesco
Gresele, Paolo
Torti, Mauro
Canobbio, Ilaria
author_facet Momi, Stefania
Canino, Jessica
Vismara, Mauro
Galgano, Luca
Falcinelli, Emanuela
Guglielmini, Giuseppe
Taranta, Giulia Ciarrocca
Guidetti, Gianni Francesco
Gresele, Paolo
Torti, Mauro
Canobbio, Ilaria
author_sort Momi, Stefania
collection PubMed
description Deep vein thrombosis results from the cooperative action of leukocytes, platelets, and endothelial cells. The proline-rich tyrosine kinase Pyk2 regulates platelet activation and supports arterial thrombosis. In this study, we combined pharmacological and genetic approaches to unravel the role of Pyk2 in venous thrombosis. We found that mice lacking Pyk2 almost completely failed to develop deep venous thrombi upon partial ligation of the inferior vena cava. Pyk2-deficient platelets displayed impaired exposure of phosphatidylserine and tissue factor expression by endothelial cells and monocytes was completely prevented by inhibition of Pyk2. In human umbilical vein endothelial cells (HUVEC), inhibition of Pyk2 hampered IL-1β-induced expression of VCAM and P-selectin, and von Willebrand factor release. Pyk2-deficient platelets showed defective adhesion on von Willebrand factor and reduced ability to bind activated HUVEC under flow. Moreover, inhibition of Pyk2 in HUVEC strongly reduced platelet adhesion. Similarly, Pyk2-deficient neutrophils were unable to efficiently roll and adhere to immobilized endothelial cells under venous flow conditions. Moreover, platelets and neutrophils from Pyk2-knockout mice showed defective ability to form heterogeneous aggregates upon stimulation, while platelet monocyte interaction occurred normally. Consequently, platelet neutrophil aggregates, abundant in blood of wild-type mice upon inferior vena cava ligation, were virtually undetectable in Pyk2-knockout mice. Finally, we found that expression of Pyk2 was required for NETosis induced by activated platelets. Altogether our results demonstrate a critical role of Pyk2 in the regulation of the coordinated thromboinflammatory responses of endothelial cells, leukocytes and platelets leading to venous thrombosis. Pyk2 may represent a novel promising target in the treatment of deep vein thrombosis.
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spelling pubmed-91529722022-06-13 Proline-rich tyrosine kinase Pyk2 regulates deep vein thrombosis Momi, Stefania Canino, Jessica Vismara, Mauro Galgano, Luca Falcinelli, Emanuela Guglielmini, Giuseppe Taranta, Giulia Ciarrocca Guidetti, Gianni Francesco Gresele, Paolo Torti, Mauro Canobbio, Ilaria Haematologica Article - Hemostasis Deep vein thrombosis results from the cooperative action of leukocytes, platelets, and endothelial cells. The proline-rich tyrosine kinase Pyk2 regulates platelet activation and supports arterial thrombosis. In this study, we combined pharmacological and genetic approaches to unravel the role of Pyk2 in venous thrombosis. We found that mice lacking Pyk2 almost completely failed to develop deep venous thrombi upon partial ligation of the inferior vena cava. Pyk2-deficient platelets displayed impaired exposure of phosphatidylserine and tissue factor expression by endothelial cells and monocytes was completely prevented by inhibition of Pyk2. In human umbilical vein endothelial cells (HUVEC), inhibition of Pyk2 hampered IL-1β-induced expression of VCAM and P-selectin, and von Willebrand factor release. Pyk2-deficient platelets showed defective adhesion on von Willebrand factor and reduced ability to bind activated HUVEC under flow. Moreover, inhibition of Pyk2 in HUVEC strongly reduced platelet adhesion. Similarly, Pyk2-deficient neutrophils were unable to efficiently roll and adhere to immobilized endothelial cells under venous flow conditions. Moreover, platelets and neutrophils from Pyk2-knockout mice showed defective ability to form heterogeneous aggregates upon stimulation, while platelet monocyte interaction occurred normally. Consequently, platelet neutrophil aggregates, abundant in blood of wild-type mice upon inferior vena cava ligation, were virtually undetectable in Pyk2-knockout mice. Finally, we found that expression of Pyk2 was required for NETosis induced by activated platelets. Altogether our results demonstrate a critical role of Pyk2 in the regulation of the coordinated thromboinflammatory responses of endothelial cells, leukocytes and platelets leading to venous thrombosis. Pyk2 may represent a novel promising target in the treatment of deep vein thrombosis. Fondazione Ferrata Storti 2022-02-10 /pmc/articles/PMC9152972/ /pubmed/35142150 http://dx.doi.org/10.3324/haematol.2021.279703 Text en Copyright© 2022 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article - Hemostasis
Momi, Stefania
Canino, Jessica
Vismara, Mauro
Galgano, Luca
Falcinelli, Emanuela
Guglielmini, Giuseppe
Taranta, Giulia Ciarrocca
Guidetti, Gianni Francesco
Gresele, Paolo
Torti, Mauro
Canobbio, Ilaria
Proline-rich tyrosine kinase Pyk2 regulates deep vein thrombosis
title Proline-rich tyrosine kinase Pyk2 regulates deep vein thrombosis
title_full Proline-rich tyrosine kinase Pyk2 regulates deep vein thrombosis
title_fullStr Proline-rich tyrosine kinase Pyk2 regulates deep vein thrombosis
title_full_unstemmed Proline-rich tyrosine kinase Pyk2 regulates deep vein thrombosis
title_short Proline-rich tyrosine kinase Pyk2 regulates deep vein thrombosis
title_sort proline-rich tyrosine kinase pyk2 regulates deep vein thrombosis
topic Article - Hemostasis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9152972/
https://www.ncbi.nlm.nih.gov/pubmed/35142150
http://dx.doi.org/10.3324/haematol.2021.279703
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