Aquaporin-1 Regulates Platelet Procoagulant Membrane Dynamics and In Vivo Thrombosis

Ejaife Agbani, Chris Williams, Yong Li, Marion van den Bosch, Samantha Moore, Adele Mauroux, Lorna Hodgson, Alan S. Verkman, Ingeborg Hers, Alastair Poole

Research output: Contribution to journalArticle (Academic Journal)peer-review

9 Citations (Scopus)
295 Downloads (Pure)

Abstract

In response to collagen stimulation, platelets use a coordinated system of fluid entry to undergo membrane ballooning, procoagulant-spreading and microvesiculation. We hypothesised that water entry was mediated by the water channel aquaporin-1 (AQP1) and aimed to determine its role in the platelet procoagulant response and thrombosis. We established that human and mouse platelets express AQP1 and localise to internal tubular membrane structures. However, deletion of AQP1 had minimal effects on collagen-induced platelet granule secretion, aggregation or membrane ballooning. Conversely, procoagulant-spreading, microvesiculation, phosphatidylserine exposure and clot formation time were significantly diminished. Furthermore, in vivo thrombus formation after FeCl3 injury to carotid arteries was also markedly suppressed in AQP1-null mice but haemostasis after tail bleeding remained normal. The mechanism involves an AQP1-mediated rapid membrane stretching during procoagulant-spreading but not ballooning, leading to calcium entry through mechanosensitive cation channels and a full procoagulant response. We conclude that AQP1 is a major regulator of the platelet procoagulant response, able to modulate coagulation after injury or pathologic stimuli without affecting other platelet functional responses or normal haemostasis. Clinically effective AQP1 inhibitors may therefore represent a novel class of antiprocoagulant antithrombotics.
Original languageEnglish
Article numbere99062
Number of pages16
JournalJCI Insight
Volume3
Issue number10
Early online date17 May 2018
DOIs
Publication statusPublished - 17 May 2018

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute

Keywords

  • Water channel
  • aquaporin-1
  • membrane ballooning
  • procoagulant-spreading
  • mechanosensitive cation channels
  • Transient receptor potential isoform C1 (TRPC1) and C6 (TRPC6)
  • piezo1
  • Synthetic biology

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