An extensional strain sensing mechanosome drives adhesion-independent platelet activation at supraphysiological hemodynamic gradients

Nurul A. Zainal Abidin, Eric K.W. Poon, Crispin Szydzik, Mariia Timofeeva, Farzan Akbaridoust, Rose J. Brazilek, Francisco J. Tovar Lopez, Xiao Ma, Chitrarth Lav, Ivan Marusic, Philip E. Thompson, Arnan Mitchell, Andrew S.H. Ooi, Justin R. Hamilton, Warwick S. Nesbitt

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Supraphysiological hemodynamics are a recognized driver of platelet activation and thrombosis at high-grade stenosis and in blood contacting circulatory support devices. However, whether platelets mechano-sense hemodynamic parameters directly in free flow (in the absence of adhesion receptor engagement), the specific hemodynamic parameters at play, the precise timing of activation, and the signaling mechanism(s) involved remain poorly elucidated. Results: Using a generalized Newtonian computational model in combination with microfluidic models of flow acceleration and quasi-homogenous extensional strain, we demonstrate that platelets directly mechano-sense acute changes in free-flow extensional strain independent of shear strain, platelet amplification loops, von Willebrand factor, and canonical adhesion receptor engagement. We define an extensional strain sensing “mechanosome” in platelets involving cooperative Ca2+ signaling driven by the mechanosensitive channel Piezo1 (as the primary strain sensor) and the fast ATP gated channel P2X1 (as the secondary signal amplifier). We demonstrate that type II PI3 kinase C2α activity (acting as a “clutch”) couples extensional strain to the mechanosome. Conclusions: Our findings suggest that platelets are adapted to rapidly respond to supraphysiological extensional strain dynamics, rather than the peak magnitude of imposed wall shear stress. In the context of overall platelet activation and thrombosis, we posit that “extensional strain sensing” acts as a priming mechanism in response to threshold levels of extensional strain allowing platelets to form downstream adhesive interactions more rapidly under the limiting effects of supraphysiological hemodynamics.

Original languageEnglish
Article number73
Number of pages22
JournalBMC Biology
Volume20
Issue number1
DOIs
Publication statusPublished - Dec 2022

Keywords

  • Extensional strain
  • Hemodynamics
  • Mechanotransduction
  • Platelet

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