Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-05817-9
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Funding
- British Heart Foundation [FS/15/36/31525, PG/11/37/28884, PG/12/49/29441]
- BBSRC [BB/I022171/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I022171/1] Funding Source: researchfish
- British Heart Foundation [FS/15/36/31525, PG/15/114/31945, PG/10/90/28636, PG/12/49/29441, PG/11/37/28884] Funding Source: researchfish
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Prostacyclin (PGI(2)) modulates platelet activation to regulate haemostasis. Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation. It was hypothesised that PGI(2) could reverse platelet spreading by actin cytoskeletal modulation, leading to reduced capability of platelet aggregates to withstand a high shear environment. Our data demonstrates that post-flow of PGI2 over activated and spread platelets on fibrinogen, identified a significant reduction in platelet surface area under high shear. Exploration of the molecular mechanisms underpinning this effect revealed that PGI(2) reversed stress fibre formation in adherent platelets, reduced platelet spreading, whilst simultaneously promoting actin nodule formation. The effects of PGI(2) on stress fibres were mimicked by the adenylyl cyclase activator forskolin and prevented by inhibitors of protein kinase A (PKA). Stress fibre formation is a RhoA dependent process and we found that treatment of adherent platelets with PGI(2) caused inhibitory phosphorylation of RhoA, reduced RhoA GTP-loading and reversal of myosin light chain phosphorylation. Phospho-RhoA was localised in actin nodules with PKA type II and a number of other phosphorylated PKA substrates. This study demonstrates that PGI(2) can reverse key platelet functions after their initial activation and identifies a novel mechanism for controlling thrombosis.
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