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Abstract
In response to collagen stimulation, platelets use a coordinated system of fluid entry to undergo membrane ballooning, procoagulant spreading, and microvesiculation. We hypothesized 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 localize 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 hemostasis 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 hemostasis. Clinically effective AQP1 inhibitors may therefore represent a novel class of antiprocoagulant antithrombotics.
Highlights
Central to the role of platelets in hemostasis and thrombosis is the dramatic morphological transformation they undergo upon contact with subendothelial collagen to generate balloon-like as well as procoagulant-spread structures [1,2,3,4,5,6]
Given that our data demonstrate the localization of AQP1 in platelets to be primarily on membranes structures (Figure 1D), we investigated whether AQP1 was involved in the actin remodeling and membrane dynamics of the platelet procoagulant response, which amplifies coagulation [4] and may be dysregulated in the absence of AQP1
The present study reveals that AQP1 accelerated the agonist-induced platelet membrane swelling and enhanced the calcium entry required for procoagulant cytoskeletal remodeling
Summary
Central to the role of platelets in hemostasis and thrombosis is the dramatic morphological transformation they undergo upon contact with subendothelial collagen to generate balloon-like as well as procoagulant-spread structures [1,2,3,4,5,6]. We showed that the mechanism underlying the morphological procoagulant transformations of activated platelets is driven by a coordinated system of Na+, Cl–, and water entry [4], and the molecular drivers of salt entry are likely calcium-activated chloride channels and nonspecific cation channels [4]. The molecular pathway for water entry required for procoagulant membrane remodeling is not clear, but water channel aquaporins are the most likely candidates. Aquaporin-1 (AQP1) is a family member with significant levels of transcript expression and detection by proteomics in platelets and megakaryocytes [8,9,10]
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