title: Vascular remodeling underlies rebleeding in hemophilic arthropathy.
abstract: Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. We investigated synovial, vascular, stromal, and cartilage changes in response to a single induced hemarthrosis in the FVIII-deficient mouse. We found soft-tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture. While soft-tissue changes were rapidly reversible, abnormal vascularity persisted for months and, surprisingly, was also seen in uninjured joints. Vascular changes in FVIII-deficient mice involved pronounced remodeling with expression of α-Smooth Muscle Actin (SMA), Endoglin (CD105), and vascular endothelial growth factor, as well as alterations of joint perfusion as determined by in vivo imaging. Vascular architecture changes and pronounced expression of α-SMA appeared unique to hemophilia, as these were not found in joint tissue obtained from mouse models of rheumatoid arthritis and osteoarthritis and from patients with the same conditions. Evidence that vascular changes in hemophilia were significantly associated with bleeding and joint deterioration was obtained prospectively by dynamic in vivo imaging with musculoskeletal ultrasound and power Doppler of 156 joints (elbows, knees, and ankles) in a cohort of 26 patients with hemophilia at baseline and during painful episodes. These observations support the hypothesis that vascular remodeling contributes significantly to bleed propagation and development of hemophilic arthropathy. Based on these findings, the development of molecular targets for angiogenesis inhibition may be considered in this disease.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California.|Department of Medicine, University of California San Diego, San Diego, California.
authors.forename: Vikas
authors.initials: V
authors.lastname: Bhat
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California.
authors.forename: Merissa
authors.initials: M
authors.lastname: Olmer
authors.affiliation: Department of Pediatrics, University of California San Diego, California.
authors.forename: Shweta
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Pediatrics, University of California San Diego, California.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Durden
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cramer
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California.
authors.forename: Richard Fw
authors.initials: RF
authors.lastname: Barnes
authors.affiliation: Department of Orthopaedic Surgery, University of California San Diego, San Diego, California.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Ball
authors.affiliation: Department of Radiology, University of California San Diego, San Diego, California.
authors.forename: Tudor H
authors.initials: TH
authors.lastname: Hughes
authors.affiliation: Orthopedic Institute for Children University of California Los Angeles, Los Angeles, California.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Silva
authors.affiliation: Orthopedic Institute for Children University of California Los Angeles, Los Angeles, California.
authors.forename: James V
authors.initials: JV
authors.lastname: Luck
authors.affiliation: General Musculoskeletal Imaging Inc, Cincinnati, Ohio.
authors.forename: Randy E
authors.initials: RE
authors.lastname: Moore
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California.
authors.forename: Laurent O
authors.initials: LO
authors.lastname: Mosnier
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California.|Department of Medicine, University of California San Diego, San Diego, California.
authors.forename: Annette
authors.initials: A
authors.lastname: von Drygalski
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000842:Ankle / Q000098:blood supply / Q000473:pathology; D004195:Disease Models, Animal; D004551:Elbow Joint / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D000071063:Endoglin; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006395:Hemarthrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006467:Hemophilia A / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007719:Knee Joint / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: D000199:Actins; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A; C544013:alpha-smooth muscle actin, mouse; C467480:vascular endothelial growth factor A, mouse; D005169:Factor VIII