Subscribe to RSS
DOI: 10.1055/s-0038-1641755
Vascular Permeability and Remodelling Coincide with Inflammatory and Reparative Processes after Joint Bleeding in Factor VIII-Deficient Mice
Funding This study was funded by a Career Development Award from the National Hemophilia Foundation (NHF) (A.v.D.), the NHF/Nicholas Cirelli Family Research Fund Judith Graham Pool Postdoctoral Research Fellowship (E.J.C.; T.W.), an American Heart Association Western States Postdoctoral Fellowship (T.W.), Bioverativ (A.v.D.) and National Institutes of Health grants CA172513, CA192656 (D.L.D.) and HL104165, HL130678 (L.O.M.).Publication History
16 December 2017
08 March 2018
Publication Date:
30 May 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201806/lookinside/thumbnails/10-1055-s-0038-1641755_170891-1.jpg)
Abstract
Vascular remodelling is a prominent feature of haemophilic arthropathy (HA) that may underlie re-bleeding, yet the nature of vascular changes and underlying mechanisms remain largely unknown. Here, we aimed to characterize synovial vascular remodelling and vessel integrity after haemarthrosis, as well as temporal changes in inflammatory and tissue-reparative pathways. Thirty acutely painful joints in patients with haemophilia (PWH) were imaged by musculoskeletal ultrasound with Power Doppler (MSKUS/PD) to detect vascular abnormalities and bloody effusions. Nineteen out of 30 painful joint episodes in PWH were associated with haemarthrosis, and abnormal vascular perfusion was unique to bleeding joints. A model of induced haemarthrosis in factor VIII (FVIII)-deficient mice was used for histological assessment of vascular remodelling (α-smooth muscle actin [αSMA] expression), and monitoring of in vivo vascular perfusion and permeability by MSKUS/PD and albumin extravasation, respectively. Inflammatory (M1) and reparative (M2) macrophage markers were quantified in murine synovium over a 10-week time course by real-time polymerase chain reaction. The abnormal vascular perfusion observed in PWH was recapitulated in FVIII-deficient mice after induced haemarthrosis. Neovascularization and increased vessel permeability were apparent 2 weeks post-bleed in FVIII-deficient mice, after a transient elevation of inflammatory macrophage M1 markers. These vascular changes subsided by week 4, while vascular remodelling, evidenced by architectural changes and pronounced αSMA expression, persisted alongside a reparative macrophage M2 response. In conclusion, haemarthrosis leads to transient inflammation coupled with neovascularization and associated vascular permeability, while subsequent tissue repair mechanisms coincide with vascular remodelling. Together, these vascular changes may promote re-bleeding and HA progression.
Keywords
haemarthrosis - vascular remodelling - vascular permeability - inflammation - tissue repair* Both authors contributed equally to this work.
-
References
- 1 Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A. ; Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12 (11) 1935-1939
- 2 Bhat V, Olmer M, Joshi S. , et al. Vascular remodeling underlies rebleeding in hemophilic arthropathy. Am J Hematol 2015; 90 (11) 1027-1035
- 3 Melchiorre D, Linari S, Innocenti M. , et al. Ultrasound detects joint damage and bleeding in haemophilic arthropathy: a proposal of a score. Haemophilia 2011; 17 (01) 112-117
- 4 Aledort LM, Haschmeyer RH, Pettersson H. ; The Orthopaedic Outcome Study Group. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. J Intern Med 1994; 236 (04) 391-399
- 5 Valentino LA, Hakobyan N. Histological changes in murine haemophilic synovitis: a quantitative grading system to assess blood-induced synovitis. Haemophilia 2006; 12 (06) 654-662
- 6 Hakobyan N, Kazarian T, Valentino LA. Synovitis in a murine model of human factor VIII deficiency. Haemophilia 2005; 11 (03) 227-232
- 7 Aznar JA, Lucía F, Abad-Franch L. , et al. Haemophilia in Spain. Haemophilia 2009; 15 (03) 665-675
- 8 Manco-Johnson MJ, Soucie JM, Gill JC. ; Joint Outcomes Committee of the Universal Data Collection, US Hemophilia Treatment Center Network. Prophylaxis usage, bleeding rates, and joint outcomes of hemophilia, 1999 to 2010: a surveillance project. Blood 2017; 129 (17) 2368-2374
- 9 Kidder W, Chang EY, M Moran C, Rose SC, von Drygalski A. Persistent vascular remodeling and leakiness are important components of the pathobiology of re-bleeding in hemophilic joints: two informative cases. Microcirculation 2016; 23 (05) 373-378
- 10 Zetterberg E, Palmblad J, Wallensten R, Morfini M, Melchiorre D, Holmström M. Angiogenesis is increased in advanced haemophilic joint disease and characterised by normal pericyte coverage. Eur J Haematol 2014; 92 (03) 256-262
- 11 Sun J, Hua B, Livingston EW. , et al. Abnormal joint and bone wound healing in hemophilia mice is improved by extending factor IX activity after hemarthrosis. Blood 2017; 129 (15) 2161-2171
- 12 Acharya SS, Schloss R, Dyke JP. , et al. Power Doppler sonography in the diagnosis of hemophilic synovitis--a promising tool. J Thromb Haemost 2008; 6 (12) 2055-2061
- 13 Walther M, Harms H, Krenn V, Radke S, Faehndrich TP, Gohlke F. Correlation of power Doppler sonography with vascularity of the synovial tissue of the knee joint in patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 2001; 44 (02) 331-338
- 14 Walther M, Harms H, Krenn V, Radke S, Kirschner S, Gohlke F. Synovial tissue of the hip at power Doppler US: correlation between vascularity and power Doppler US signal. Radiology 2002; 225 (01) 225-231
- 15 Arciniegas E, Frid MG, Douglas IS, Stenmark KR. Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2007; 293 (01) L1-L8
- 16 Mauser-Bunschoten EP, Zijl JA, Mali W, van Rinsum AC, van den Berg HM, Roosendaal G. Successful treatment of severe bleeding in hemophilic target joints by selective angiographic embolization. Blood 2005; 105 (07) 2654-2657
- 17 Wyseure T, Mosnier LO, von Drygalski A. Advances and challenges in hemophilic arthropathy. Semin Hematol 2016; 53 (01) 10-19
- 18 Sen D, Chapla A, Walter N, Daniel V, Srivastava A, Jayandharan GR. Nuclear factor (NF)-κB and its associated pathways are major molecular regulators of blood-induced joint damage in a murine model of hemophilia. J Thromb Haemost 2013; 11 (02) 293-306
- 19 Narkbunnam N, Sun J, Hu G. , et al. IL-6 receptor antagonist as adjunctive therapy with clotting factor replacement to protect against bleeding-induced arthropathy in hemophilia. J Thromb Haemost 2013; 11 (05) 881-893
- 20 Roosendaal G, Vianen ME, Wenting MJ. , et al. Iron deposits and catabolic properties of synovial tissue from patients with haemophilia. J Bone Joint Surg Br 1998; 80 (03) 540-545
- 21 Acharya SS, Kaplan RN, Macdonald D, Fabiyi OT, DiMichele D, Lyden D. Neoangiogenesis contributes to the development of hemophilic synovitis. Blood 2011; 117 (08) 2484-2493
- 22 Manon-Jensen T, Karsdal MA, Nielsen LN. , et al. Altered collagen turnover in factor VIII-deficient rats with hemophilic arthropathy identifies potential novel serological biomarkers in hemophilia. J Thromb Haemost 2016; 14 (12) 2419-2429
- 23 Manon-Jensen T, Hua BL, Olsen EHN. , et al. Increased basement membrane turnover and strongly attenuated interstitial matrix turnover is a key pathological feature of haemophilia. Haemophilia 2017; 23 (06) e515-e518
- 24 Hua B, Olsen EHN, Sun S. , et al. Serological biomarkers detect active joint destruction and inflammation in patients with haemophilic arthropathy. Haemophilia 2017; 23 (04) e294-e300
- 25 Bonnefoy O, Diris B, Moinard M, Aunoble S, Diard F, Hauger O. Acute knee trauma: role of ultrasound. Eur Radiol 2006; 16 (11) 2542-2548
- 26 Martinoli C, Della Casa Alberighi O, Di Minno G. , et al. Development and definition of a simplified scanning procedure and scoring method for Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US). Thromb Haemost 2013; 109 (06) 1170-1179
- 27 Backhaus M, Ohrndorf S, Kellner H. , et al. Evaluation of a novel 7-joint ultrasound score in daily rheumatologic practice: a pilot project. Arthritis Rheum 2009; 61 (09) 1194-1201
- 28 Brown BD, Shi CX, Rawle FE. , et al. Factors influencing therapeutic efficacy and the host immune response to helper-dependent adenoviral gene therapy in hemophilia A mice. J Thromb Haemost 2004; 2 (01) 111-118
- 29 von Drygalski A, Furlan-Freguia C, Ruf W, Griffin JH, Mosnier LO. Organ-specific protection against lipopolysaccharide-induced vascular leak is dependent on the endothelial protein C receptor. Arterioscler Thromb Vasc Biol 2013; 33 (04) 769-776
- 30 von Drygalski A, Furlan-Freguia C, Mosnier LO, Yegneswaran S, Ruf W, Griffin JH. Infrared fluorescence for vascular barrier breach in vivo--a novel method for quantitation of albumin efflux. Thromb Haemost 2012; 108 (05) 981-991
- 31 Joshi S, Singh AR, Zulcic M. , et al. Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo. PLoS One 2014; 9 (04) e95893
- 32 Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008; 3 (06) 1101-1108
- 33 Dinarvand P, Hassanian SM, Qureshi SH. , et al. Polyphosphate amplifies proinflammatory responses of nuclear proteins through interaction with receptor for advanced glycation end products and P2Y1 purinergic receptor. Blood 2014; 123 (06) 935-945
- 34 Bae JS, Lee W, Rezaie AR. Polyphosphate elicits pro-inflammatory responses that are counteracted by activated protein C in both cellular and animal models. J Thromb Haemost 2012; 10 (06) 1145-1151
- 35 Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci 2008; 13: 453-461
- 36 Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 2014; 6: 13
- 37 Chang NC, Hung SI, Hwa KY. , et al. A macrophage protein, Ym1, transiently expressed during inflammation is a novel mammalian lectin. J Biol Chem 2001; 276 (20) 17497-17506
- 38 Lucas R, Fulton D, Caldwell RW, Romero MJ. Arginase in the vascular endothelium: friend or foe?. Front Immunol 2014; 5: 589
- 39 Durante W. Role of arginase in vessel wall remodeling. Front Immunol 2013; 4: 111
- 40 Greenberg JI, Shields DJ, Barillas SG. , et al. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 2008; 456 (7223): 809-813
- 41 Mason DP, Kenagy RD, Hasenstab D. , et al. Matrix metalloproteinase-9 overexpression enhances vascular smooth muscle cell migration and alters remodeling in the injured rat carotid artery. Circ Res 1999; 85 (12) 1179-1185
- 42 Szekanecz Z, Koch AE. Macrophages and their products in rheumatoid arthritis. Curr Opin Rheumatol 2007; 19 (03) 289-295
- 43 Nieuwenhuizen L, Schutgens RE, Coeleveld K. , et al. Hemarthrosis in hemophilic mice results in alterations in M1-M2 monocyte/macrophage polarization. Thromb Res 2014; 133 (03) 390-395
- 44 He H, Mack JJ, Güç E. , et al. Perivascular macrophages limit permeability. Arterioscler Thromb Vasc Biol 2016; 36 (11) 2203-2212
- 45 Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM. Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis 2014; 17 (01) 109-118
- 46 Zajac E, Schweighofer B, Kupriyanova TA. , et al. Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9. Blood 2013; 122 (25) 4054-4067
- 47 Milam KE, Parikh SM. The angiopoietin-Tie2 signaling axis in the vascular leakage of systemic inflammation. Tissue Barriers 2015; 3 (1-2): e957508
- 48 Valentino LA, Hakobyan N, Kazarian T, Jabbar KJ, Jabbar AA. Experimental haemophilic synovitis: rationale and development of a murine model of human factor VIII deficiency. Haemophilia 2004; 10 (03) 280-287
- 49 Szekanecz Z, Koch AE. Mechanisms of disease: angiogenesis in inflammatory diseases. Nat Clin Pract Rheumatol 2007; 3 (11) 635-643
- 50 Szekanecz Z, Koch AE. Vascular involvement in rheumatic diseases: ‘vascular rheumatology’. Arthritis Res Ther 2008; 10 (05) 224
- 51 Bonnet CS, Walsh DA. Osteoarthritis, angiogenesis and inflammation. Rheumatology (Oxford) 2005; 44 (01) 7-16
- 52 Simkin PA, Bassett JE. Pathways of microvascular permeability in the synovium of normal and diseased human knees. J Rheumatol 2011; 38 (12) 2635-2642