TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding
Tine Wyseure, Tingyi Yang, Jenny Y. Zhou, Esther J. Cooke, Bettina Wanko, Merissa Olmer, Ruchi Agashe, Yosuke Morodomi, Niels Behrendt, Martin Lotz, John Morser, Annette von Drygalski, Laurent O. Mosnier
Tine Wyseure, Tingyi Yang, Jenny Y. Zhou, Esther J. Cooke, Bettina Wanko, Merissa Olmer, Ruchi Agashe, Yosuke Morodomi, Niels Behrendt, Martin Lotz, John Morser, Annette von Drygalski, Laurent O. Mosnier
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Research Article Angiogenesis Hematology

TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding

Abstract

Excessive vascular remodeling is characteristic of hemophilic arthropathy (HA) and may contribute to joint bleeding and the progression of HA. Mechanisms for pathological vascular remodeling after hemophilic joint bleeding are unknown. In hemophilia, activation of thrombin-activatable fibrinolysis inhibitor (TAFI) is impaired, which contributes to joint bleeding and may also underlie the aberrant vascular remodeling. Here, hemophilia A (factor VIII–deficient; FVIII-deficient) mice or TAFI-deficient mice with transient (antibody-induced) hemophilia A were used to determine the role of FVIII and TAFI in vascular remodeling after joint bleeding. Excessive vascular remodeling and vessel enlargement persisted in FVIII-deficient and TAFI-deficient mice, but not in transient hemophilia WT mice, after similar joint bleeding. TAFI-overexpression in FVIII-deficient mice prevented abnormal vessel enlargement and vascular leakage. Age-related vascular changes were observed with FVIII or TAFI deficiency and correlated positively with bleeding severity after injury, supporting increased vascularity as a major contributor to joint bleeding. Antibody-mediated inhibition of uPA also prevented abnormal vascular remodeling, suggesting that TAFI’s protective effects include inhibition of uPA-mediated plasminogen activation. In conclusion, the functional TAFI deficiency in hemophilia drives maladaptive vascular remodeling in the joints after bleeding. These mechanistic insights allow targeted development of potentially new strategies to normalize vascularity and control rebleeding in HA.

Authors

Tine Wyseure, Tingyi Yang, Jenny Y. Zhou, Esther J. Cooke, Bettina Wanko, Merissa Olmer, Ruchi Agashe, Yosuke Morodomi, Niels Behrendt, Martin Lotz, John Morser, Annette von Drygalski, Laurent O. Mosnier

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Figure 3

Joint blood flow increases spontaneously with aging in TAFI-deficient mice.

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Joint blood flow increases spontaneously with aging in TAFI-deficient mi...
(A) Analysis of knee joint vascularity at baseline (no injury) by ultrasound power Doppler (PD) (pixel2; median ± 95% CI) in BALB/c WT (n = 17–58), BALB/c FVIII-KO (n = 10–61), C57Bl/6J WT (n = 26–41), and C57Bl/6J TAFI-KO (n = 25–89) mice at 3–4 months (“3”), 8–10 month (“9”), and 18–22 months (“18”) of age. PD signal was obtained from recording at the medial side of the right knee joint. Each point represents an individual mouse. (B) Analysis of age-related increases in PD signal (pixel2; median) in joints of BALB/c FVIII-KO mice (n = 10–61) and C57Bl/6J TAFI-KO (n = 25–89) compared with their respective age-matched WT controls (n = 17–58 for BALB/c WT and n = 26–41 for C57Bl/6J WT) at 3–4 months (“3”), 8–10 month (“9”), and 18–22 months (“18”). Statistical significance is shown versus age-matched WT control mice. (C and D) Representative images of PD recordings at > 18 months for (C) BALB/c FVIII-KO mice and (D) C57Bl/6J TAFI-KO and their respective age-matched WT controls. The intensity of vascular flow is pseudocolored from low flow (red) to high flow (yellow) as indicated. Original scaled dimensions are 0.86 cm (w) × 0.63 cm (h). Data were analyzed using Kruskal-Wallis with Dunn’s multiple comparisons test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.