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Mechanisms of vascular permeability and remodeling associated with hemarthrosis in factor VIII-deficient mice.

ABSTRACT: 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.

SUBMITTER: Cooke EJ

PROVIDER: S-EPMC6824926 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Mechanisms of vascular permeability and remodeling associated with hemarthrosis in factor VIII-deficient mice.

Cooke Esther J EJ Wyseure Tine T Zhou Jenny Y JY Gopal Srila S Nasamran Chanond A CA Fisch Kathleen M KM Manon-Jensen Tina T Karsdal Morten A MA Mosnier Laurent O LO von Drygalski Annette A

Journal of thrombosis and haemostasis : JTH 20190809 11

<h4>Background</h4>Vascular remodeling associated with hemophilic arthropathy (HA) may contribute to bleed propagation, but the mechanisms remain poorly understood.<h4>Objectives</h4>To explore molecular mechanisms of HA and the effects of hemostasis correction on synovial vascular remodeling after joint injury in hypocoagulable mice.<h4>Methods</h4>Factor VIII (FVIII)-deficient mice +/- FVIII treatment and hypocoagulable wild-type mice (<sup>Hypo</sup> BALB/c) were subjected to subpatellar punc ...[more]

PMID: 31301687

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Project description:Background and purposeBrain edema is an important underlying pathology in acute stroke, especially when comorbidities are present. VEGF (Vascular endothelial growth factor) signaling is implicated in edema. This study investigated whether obesity impacts VEGF signaling and brain edema, as well as whether VEGF inhibition alters stroke outcome in obese subjects.MethodsHigh-fat diet-induced obese mice were subjected to a transient middle cerebral artery occlusion. VEGF-A and VEGFR2 (receptor) expression, infarct volume, and swelling were measured 3 days post-middle cerebral artery occlusion. To validate the effect of an anti-VEGF strategy, we used aflibercept, a fusion protein that has a VEGF-binding domain and acts as a decoy receptor, in human umbilical vein endothelial cells stimulated with rVEGF (recombinant VEGF; 50 ng/mL) for permeability and tube formation. In vivo, aflibercept (10 mg/kg) or IgG control was administered in obese mice 3 hours after transient 30 minutes middle cerebral artery occlusion. Blood-brain barrier integrity was assessed by IgG staining and dextran extravasation in the postischemic brain. A separate cohort of nonobese (lean) mice was subjected to 40 minutes middle cerebral artery occlusion to test the effect of aflibercept on malignant infarction.ResultsCompared with lean mice, obese mice had increased mortality, infarct volume, swelling, and blood-brain barrier disruption. These outcomes were also associated with increased VEGF-A and VEGFR2 expression. Aflibercept reduced VEGF-A-stimulated permeability and tube formation in human umbilical vein endothelial cells. Compared with the IgG-treated controls, mice treated with aflibercept had reduced mortality rates (40% versus 17%), hemorrhagic transformation (43% versus 27%), and brain swelling (28% versus 18%), although the infarct size was similar. In nonobese mice with large stroke, aflibercept neither improved nor exacerbated stroke outcomes.ConclusionsThe study demonstrates that aflibercept selectively attenuates stroke-induced brain edema and vascular permeability in obese mice. These findings suggest the repurposing of aflibercept to reduce obesity-enhanced brain edema in acute stroke.

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Mechanisms of vascular permeability and remodeling associated with hemarthrosis in factor VIII-deficient mice.

Publications

Mechanisms of vascular permeability and remodeling associated with hemarthrosis in factor VIII-deficient mice.

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