title: Progression of the prothrombotic state in aging Bmal1-deficient mice.
abstract: OBJECTIVE
  The goal of this study was to examine the functional relationship between aging endothelium and thrombogenicity in a mouse model of premature aging.
  
  
  RESULTS
  Coagulation tests and factors, blood cell counts, aorta endothelial function, aorta gene expression, and FeCl(3)-induced thrombosis in mesenteric blood vessels were analyzed in 10- to 30-week-old brain and muscle ARNT-like protein-1 (Bmal1)-deficient (knockout [KO]) mice and wild-type littermates. Ten-week-old KO mice manifested shortened prothrombin times (9.7 versus 11.3 seconds in wild-type) and elevated plasma fibrinogen (264 versus 172 mg/dL). At 30 weeks, factor VII (198% versus 149%), and platelet counts (2049 versus 1354 K/μL) were increased in KO mice. Gene deficiency reduced the vasoactive nitric oxide production at 10 and 30 weeks and tended to reduce and increase the protein expression of thrombomodulin and von Willebrand factor, respectively, with aging. Shortened venular and arteriolar occlusion times on FeCl(3)-induced injury in 10-week-old KO mice confirmed higher thrombogenicity, culminating in priapism, observed in 60% of 25- to 30-week-old KO males.
  
  
  CONCLUSIONS
  Endothelial dysfunction and a hypercoagulable state cause early arterial and venous thrombogenicity in Bmal1 KO mice. With aging, progressive endothelial dysfunction, rising platelet counts, and high factor VII further enhance thrombogenicity, provoking priapism.
authors.affiliation: Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Bianca
authors.initials: B
authors.lastname: Hemmeryckx
authors.forename: Cor E
authors.initials: CE
authors.lastname: Van Hove
authors.forename: Paul
authors.initials: P
authors.lastname: Fransen
authors.forename: Jan
authors.initials: J
authors.lastname: Emmerechts
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kauskot
authors.forename: Hidde
authors.initials: H
authors.lastname: Bult
authors.forename: H Roger
authors.initials: HR
authors.lastname: Lijnen
authors.forename: Marc F
authors.initials: MF
authors.lastname: Hoylaerts
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency* / Q000235:genetics; D000375:Aging / Q000502:physiology; D019588:Aging, Premature / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D005340:Fibrinogen / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010976:Platelet Count; D011517:Prothrombin Time; D018180:Thrombomodulin / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism* / Q000503:physiopathology*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D018180:Thrombomodulin; D014841:von Willebrand Factor; D005340:Fibrinogen