Hypoxia suppresses platelet activity through GPVI downregulation but paradoxically enhances arterial thrombosis via elevated vWF
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ID: 315873
2026
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Abstract
AIMS: Hypoxia is associated with thrombosis, yet its effects on platelet function remain controversial due to variable experimental conditions. In this study, we systematically examined the effects of graded normobaric hypoxia on platelet function and arterial thrombosis in mice. METHODS AND RESULTS: Exposure to 8% O2 for 6 days increased red blood cell counts, hemoglobin, and hematocrit, recapitulating human hypoxic adaptation. Platelets from hypoxic mice show reduced activation and aggregation in response to multiple agonists, including thrombin and collagen-related peptide, with defects accentuated by more severe (8% vs. 12% O2) or prolonged (6-day vs. 4-day) hypoxia and most pronounced after glycoprotein VI (GPVI) stimulation. Similar platelet dysfunction occurs in humans after 4-day hypoxia (∼12% O2) followed by 4-day normoxia. Quantitative mass spectrometry identifies downregulation of lysozyme, Hsp90 signaling molecules, and GPVI. Pathway and systems-level network analyses reveal significant downregulation of Hsp90-involved protein folding and GPVI-mediated signaling pathways. Deletion of platelet lysozyme or Hsp90β, however, minimally affects platelet function, indicating regulation by multiple signaling pathways under hypoxia. We confirmed that GPVI levels are significantly reduced in platelets, while ADAM10 levels remain unchanged, suggesting hypoxia-induced GPVI downregulation. Hypoxic blood forms smaller thrombi on collagen under arterial shear. Paradoxically, hypoxic mice exhibit enhanced arterial thrombosis and shortened tail bleeding times. Biochemical and mass spectrometry analyses of mouse plasma demonstrate elevated circulating von Willebrand factor under hypoxia. CONCLUSION: These results uncover a paradox under hypoxia: despite GPVI downregulation and impaired agonist-induced platelet activation, elevated plasma von Willebrand factor drives enhanced arterial thrombosis. This multilayered regulation provides mechanistic insight into hypoxia-associated thrombotic risk and may inform therapeutic strategies.
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| Authors | Vishwanath Jha, Jae-Sung Kim, Muteen Ahmed, Joseph E Italiano, Babak Razani, J Cho |
| Journal | cardiovascular research |
| Year | 2026 |
| DOI |
10.1093/cvr/cvag123
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| URL | |
| Keywords | Keywords not found |
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