Mechanisms of vascular permeability and remodeling associated with hemarthrosis in factor VIII‐deficient mice
| Autor: | Srila Gopal, Morten A. Karsdal, Tine Wyseure, Chanond A Nasamran, Esther J Cooke, Kathleen M. Fisch, Tina Manon-Jensen, Jenny Y Zhou, Annette von Drygalski, Laurent O. Mosnier |
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| Rok vydání: | 2019 |
| Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities Pathology medicine.medical_specialty Time Factors Angiogenesis Vascular permeability Vascular Remodeling 030204 cardiovascular system & hematology Hemophilia A Article Hemostatics Capillary Permeability Extracellular matrix 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Vascularity hemic and lymphatic diseases Hemarthrosis Animals Medicine Evans Blue Mice Knockout Hemostasis Mice Inbred BALB C Factor VIII business.industry Synovial Membrane Hematology medicine.disease Extravasation Disease Models Animal chemistry Female medicine.symptom business |
| Zdroj: | J Thromb Haemost |
| ISSN: | 1538-7836 |
| Popis: | Background Vascular remodeling associated with hemophilic arthropathy (HA) may contribute to bleed propagation, but the mechanisms remain poorly understood. Objectives To explore molecular mechanisms of HA and the effects of hemostasis correction on synovial vascular remodeling after joint injury in hypocoagulable mice. Methods Factor VIII (FVIII)-deficient mice +/- FVIII treatment and hypocoagulable wild-type mice (Hypo BALB/c) were subjected to subpatellar puncture. Hypo BALB/c mice were treated with warfarin and anti-FVIII before injury, after which warfarin was continued for 2 weeks or reversed +/- continuous anti-FVIII until harvest. Synovial vascularity was analyzed at baseline and 2 to 4 weeks post injury by histology, musculoskeletal ultrasound with power Doppler (microvascular flow), and Evans blue extravasation (vascular permeability). Synovial gene expression and systemic markers of vascular collagen turnover were studied in FVIII-deficient mice by RNA sequencing and enzyme-linked immunosorbent assay. Results Vascular changes occurred in FVIII-deficient and Hypo BALB/c mice after injury with minimal effect of hemostasis correction. Increased vascular permeability was only significant in FVIII-deficient mice, who exhibited more pronounced vascular remodeling than Hypo BALB/c mice despite similar bleed volumes. FVIII-deficient mice exhibited a strong transcriptional response in synovium that was only partially affected by FVIII treatment and involved genes relating to angiogenesis and extracellular matrix remodeling, with vascular collagen turnover markers detected systemically. Conclusions Intact hemostasis at the time of hemarthrosis and during healing are both critical to prevent vascular remodeling, which appears worse with severe and prolonged FVIII deficiency. Unbiased RNA sequencing revealed potential targets for intervention and biomarker development to improve management of HA. |
| Databáze: | OpenAIRE |
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