title: Novel insights into the development of atherosclerosis in hemophilia A mouse models.
abstract: BACKGROUND
  Cardiovascular diseases in aging people with hemophilia (PWH) represent a growing concern. The underlying hypocoagulability probably provides a protective effect against acute thrombus formation, but the limited data available show no preventive effect against the development of atherogenesis in PWH. Atherosclerosis-prone mice are attractive tools for the study of atherosclerosis development, and may provide insights into disease progression in PWH.
  
  
  METHODS
  Severe hemophilia A (factor VIII-deficient [FVIII(o)]) mice were crossed with mice lacking apolipoprotein E (ApoE(-/-)) or mice lacking the LDL receptor (LDLR(-/-)), and then compared to hemostatically normal littermate controls. After mice had received atherogenic diets for 8, 22 or 37 weeks, atherosclerotic lesion size and phenotypic characterization were analyzed in the aortic sinus and whole aortas.
  
  
  RESULTS
  ApoE(-/-)/FVIII(o) mice showed a time-dependent protective effect against the development of atherosclerosis, beginning after 22 diet-weeks and persisting to 37 diet-weeks in both the aorta sinus and whole aorta as compared with ApoE(-/-) mice. Notably, the FVIII deficiency did not influence the progression of atherosclerosis in the FVIII(o)/LDLR(-/-) model as compared with controls at early or late time points.
  
  
  CONCLUSIONS
  Hypocoagulability ameliorates vascular disease in the ApoE-deficient model in a lipid-independent manner. Interestingly, FVIII deficiency did not affect the development of atherosclerosis in LDLR(-/-) mice. In contrast to the ApoE model, the LDLR model resembles the lipid profile that is commonly observed in humans with atherosclerosis. These findings, to a certain extent, support the notion of atherosclerosis development in the complete absence of FVIII.
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil.
authors.forename: D R
authors.initials: DR
authors.lastname: Fabri
authors.forename: E V
authors.initials: EV
authors.lastname: de Paula
authors.forename: D S P
authors.initials: DS
authors.lastname: Costa
authors.forename: J M
authors.initials: JM
authors.lastname: Annichino-Bizzacchi
authors.forename: V R
authors.initials: VR
authors.lastname: Arruda
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001777:Blood Coagulation / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006467:Hemophilia A / Q000097:blood / Q000150:complications* / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D011973:Receptors, LDL; D005169:Factor VIII; D002784:Cholesterol