ERK2 activation in arteriolar and venular murine thrombosis: Platelet receptor GPIb vs. P2X1

C. Oury, K. Daenens, H. Hu, E. Tóth-Zsámboki, M. Bryckaerth, Marc F. Hoylaerts

Research output: Contribution to journalArticle

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Abstract

The functional significance of extracellular signal regulated kinase 2 (ERK2) activation was investigated during shear induced human platelet aggregation (SIPA) in vitro and during shear controlled thrombosis in vivo in intestinal arterioles and venules of wild type (WT) and transgenic (TG) mice with platelet-specific overexpression of human P2X1 (TG). In SIPA, ERK2 was rapidly phosphorylated during GPIb stimulation, its activation contributing to SIPA for 50%, independently of P2X1 regulation. Thrombotic occlusion of injured arterioles occurred considerably faster inTG(4.3 ± 2.3 min) than in WT (38 ± 8 min) arterioles, but occlusion times in TG (19 ± 12) and WT (48 ± 4.5 min) venules differed less. Both the αβ-meATP triggered desensitization of platelet P2X1, as well as P2X1 antagonism by NF279 or NF449 prolonged mean occlusion to about 75 min inWT and 65 min in TG arterioles, but venular occlusion times were less affected. Preventing ERK2 activation by U0126 prolonged occlusion times in TG (41 ± 10 min) and WT (51 ± 17) arterioles more than in TG (46 ± 5 min) and WT (56 ± 6 min) venules, uncovering a role for ERK2 in shear controlled thrombosis. Antagonism of GPIb by a recombinant murine von Willebrand factor (VWF)-A1 fragment prolonged occlusion times to comparable values, ranging from 55 to 58 min, both in TG and WT arterioles and venules. Further inhibition strategies, combining VWF-A1, U0126 and NF449 in WT and TG mice and resulting in occlusion in various time windows, identified that inhibition by VWF-A1 largely abrogated the ERK2 contribution to thrombosis. In conclusion, P2X1 and ERK2 both participate in shear stress controlled thrombosis, but ERK2 activation is initiated predominantly via GPIb-VWF interactions.

Original languageEnglish
Pages (from-to)443-452
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume4
Issue number2
DOIs
Publication statusPublished - Feb 2006

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Mitogen-Activated Protein Kinase 1
Arterioles
Thrombosis
Blood Platelets
Venules
von Willebrand Factor
Platelet Aggregation
Transgenic Mice

Keywords

  • Degranulation
  • Nucleotides
  • Platelet
  • Shear stress
  • Signaling
  • Thrombosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

ERK2 activation in arteriolar and venular murine thrombosis : Platelet receptor GPIb vs. P2X1. / Oury, C.; Daenens, K.; Hu, H.; Tóth-Zsámboki, E.; Bryckaerth, M.; Hoylaerts, Marc F.

In: Journal of Thrombosis and Haemostasis, Vol. 4, No. 2, 02.2006, p. 443-452.

Research output: Contribution to journalArticle

Oury, C. ; Daenens, K. ; Hu, H. ; Tóth-Zsámboki, E. ; Bryckaerth, M. ; Hoylaerts, Marc F. / ERK2 activation in arteriolar and venular murine thrombosis : Platelet receptor GPIb vs. P2X1. In: Journal of Thrombosis and Haemostasis. 2006 ; Vol. 4, No. 2. pp. 443-452.
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