Projects per year
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 language | English |
---|---|
Article number | 73 |
Number of pages | 22 |
Journal | BMC Biology |
Volume | 20 |
Issue number | 1 |
DOIs | |
Publication status | Published - Dec 2022 |
Keywords
- Extensional strain
- Hemodynamics
- Mechanotransduction
- Platelet
Projects
- 1 Active
-
Development of a Microfluidic Blood Platelet Analyser
Nesbitt, W., Mitchell, A., Nandurkar, H., Hamilton, J., Thompson, P., Tran, H., Elliott, S. & Macfarlane, I.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/19 → 31/07/23
Project: Research
Equipment
-
Monash Micro Imaging
Stephen Firth (Manager), Alex Fulcher (Operator), Oleks Chernyavskiy (Operator), Margaret Rzeszutek (Other), David Potter (Manager), Volker Hilsenstein (Operator), Juan Nunez-Iglesias (Other), Stephen Cody (Manager), Irena Carmichael (Operator), Betty Kouskousis (Other), Sarah Creed (Manager) & Giulia Ballerin (Operator)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility