Abstract

Platelet interaction with collagens, via von Willebrand factor, is a potent trigger of shear-dependent thrombus formation mediated by subsequent engagement of the signaling collagen receptor glycoprotein (GP)VI, enforced by integrin α2β1. Protein tyrosine kinase Syk is central in the GPVI-induced signaling pathway, leading to elevated cytosolic Ca2+. We aimed to determine the Syk-mediated thrombogenic activity of several collagen peptides and (fibrillar) type I and III collagens. High-shear perfusion of blood over microspots of these substances resulted in thrombus formation, which was assessed by eight parameters and was indicative of platelet adhesion, activation, aggregation, and contraction, which were affected by the Syk inhibitor PRT-060318. In platelet suspensions, only collagen peptides containing the consensus GPVI-activating sequence (GPO)n and Horm-type collagen evoked Syk-dependent Ca2+ rises. In whole blood under flow, Syk inhibition suppressed platelet activation and aggregation parameters for the collagen peptides with or without a (GPO)n sequence and for all of the collagens. Prediction models based on a regression analysis indicated a mixed role of GPVI in thrombus formation on fibrillar collagens, which was abolished by Syk inhibition. Together, these findings indicate that GPVI-dependent signaling through Syk supports platelet activation in thrombus formation on collagen-like structures regardless of the presence of a (GPO)n sequence.

Original languageEnglish
Article number2788
Number of pages20
JournalInternational journal of molecular sciences
Volume20
Issue number11
DOIs
Publication statusPublished - 1 Jun 2019

Keywords

  • ACTIVATION
  • ADHESION
  • BINDING
  • FIBRIN
  • GPVI
  • IDENTIFICATION
  • RECEPTOR
  • RECOGNIZES
  • SRC
  • calcium
  • collagen
  • glycoprotein VI
  • platelet activation
  • protein tyrosine kinase
  • thrombus

Cite this

@article{244113eeda5f417baab65787fb4cebb3,
title = "Role of Platelet Glycoprotein VI and Tyrosine Kinase Syk in Thrombus Formation on Collagen-Like Surfaces",
abstract = "Platelet interaction with collagens, via von Willebrand factor, is a potent trigger of shear-dependent thrombus formation mediated by subsequent engagement of the signaling collagen receptor glycoprotein (GP)VI, enforced by integrin α2β1. Protein tyrosine kinase Syk is central in the GPVI-induced signaling pathway, leading to elevated cytosolic Ca2+. We aimed to determine the Syk-mediated thrombogenic activity of several collagen peptides and (fibrillar) type I and III collagens. High-shear perfusion of blood over microspots of these substances resulted in thrombus formation, which was assessed by eight parameters and was indicative of platelet adhesion, activation, aggregation, and contraction, which were affected by the Syk inhibitor PRT-060318. In platelet suspensions, only collagen peptides containing the consensus GPVI-activating sequence (GPO)n and Horm-type collagen evoked Syk-dependent Ca2+ rises. In whole blood under flow, Syk inhibition suppressed platelet activation and aggregation parameters for the collagen peptides with or without a (GPO)n sequence and for all of the collagens. Prediction models based on a regression analysis indicated a mixed role of GPVI in thrombus formation on fibrillar collagens, which was abolished by Syk inhibition. Together, these findings indicate that GPVI-dependent signaling through Syk supports platelet activation in thrombus formation on collagen-like structures regardless of the presence of a (GPO)n sequence.",
keywords = "ACTIVATION, ADHESION, BINDING, FIBRIN, GPVI, IDENTIFICATION, RECEPTOR, RECOGNIZES, SRC, calcium, collagen, glycoprotein VI, platelet activation, protein tyrosine kinase, thrombus",
author = "Jooss, {Natalie J} and {De Simone}, Ilaria and Isabella Provenzale and Fern{\'a}ndez, {Delia I} and Brouns, {Sanne L N} and Farndale, {Richard W} and Henskens, {Yvonne M C} and Kuijpers, {Marijke J E} and {Ten Cate}, Hugo and {van der Meijden}, {Paola E J} and Rachel Cavill and Heemskerk, {Johan W M}",
year = "2019",
month = "6",
day = "1",
doi = "10.3390/ijms20112788",
language = "English",
volume = "20",
journal = "International Journal of Molecular Sciences",
issn = "1422-0067",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "11",

}

TY - JOUR

T1 - Role of Platelet Glycoprotein VI and Tyrosine Kinase Syk in Thrombus Formation on Collagen-Like Surfaces

AU - Jooss, Natalie J

AU - De Simone, Ilaria

AU - Provenzale, Isabella

AU - Fernández, Delia I

AU - Brouns, Sanne L N

AU - Farndale, Richard W

AU - Henskens, Yvonne M C

AU - Kuijpers, Marijke J E

AU - Ten Cate, Hugo

AU - van der Meijden, Paola E J

AU - Cavill, Rachel

AU - Heemskerk, Johan W M

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Platelet interaction with collagens, via von Willebrand factor, is a potent trigger of shear-dependent thrombus formation mediated by subsequent engagement of the signaling collagen receptor glycoprotein (GP)VI, enforced by integrin α2β1. Protein tyrosine kinase Syk is central in the GPVI-induced signaling pathway, leading to elevated cytosolic Ca2+. We aimed to determine the Syk-mediated thrombogenic activity of several collagen peptides and (fibrillar) type I and III collagens. High-shear perfusion of blood over microspots of these substances resulted in thrombus formation, which was assessed by eight parameters and was indicative of platelet adhesion, activation, aggregation, and contraction, which were affected by the Syk inhibitor PRT-060318. In platelet suspensions, only collagen peptides containing the consensus GPVI-activating sequence (GPO)n and Horm-type collagen evoked Syk-dependent Ca2+ rises. In whole blood under flow, Syk inhibition suppressed platelet activation and aggregation parameters for the collagen peptides with or without a (GPO)n sequence and for all of the collagens. Prediction models based on a regression analysis indicated a mixed role of GPVI in thrombus formation on fibrillar collagens, which was abolished by Syk inhibition. Together, these findings indicate that GPVI-dependent signaling through Syk supports platelet activation in thrombus formation on collagen-like structures regardless of the presence of a (GPO)n sequence.

AB - Platelet interaction with collagens, via von Willebrand factor, is a potent trigger of shear-dependent thrombus formation mediated by subsequent engagement of the signaling collagen receptor glycoprotein (GP)VI, enforced by integrin α2β1. Protein tyrosine kinase Syk is central in the GPVI-induced signaling pathway, leading to elevated cytosolic Ca2+. We aimed to determine the Syk-mediated thrombogenic activity of several collagen peptides and (fibrillar) type I and III collagens. High-shear perfusion of blood over microspots of these substances resulted in thrombus formation, which was assessed by eight parameters and was indicative of platelet adhesion, activation, aggregation, and contraction, which were affected by the Syk inhibitor PRT-060318. In platelet suspensions, only collagen peptides containing the consensus GPVI-activating sequence (GPO)n and Horm-type collagen evoked Syk-dependent Ca2+ rises. In whole blood under flow, Syk inhibition suppressed platelet activation and aggregation parameters for the collagen peptides with or without a (GPO)n sequence and for all of the collagens. Prediction models based on a regression analysis indicated a mixed role of GPVI in thrombus formation on fibrillar collagens, which was abolished by Syk inhibition. Together, these findings indicate that GPVI-dependent signaling through Syk supports platelet activation in thrombus formation on collagen-like structures regardless of the presence of a (GPO)n sequence.

KW - ACTIVATION

KW - ADHESION

KW - BINDING

KW - FIBRIN

KW - GPVI

KW - IDENTIFICATION

KW - RECEPTOR

KW - RECOGNIZES

KW - SRC

KW - calcium

KW - collagen

KW - glycoprotein VI

KW - platelet activation

KW - protein tyrosine kinase

KW - thrombus

U2 - 10.3390/ijms20112788

DO - 10.3390/ijms20112788

M3 - Article

C2 - 31181592

VL - 20

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 11

M1 - 2788

ER -