title: Molecular Imaging of Platelet-Endothelial Interactions and Endothelial von Willebrand Factor in Early and Mid-Stage Atherosclerosis.
abstract: BACKGROUND
  Nonthrombotic platelet-endothelial interactions may contribute to atherosclerotic plaque development, although in vivo studies examining mechanism without platelet preactivation are lacking. Using in vivo molecular imaging at various stages of atherosclerosis, we quantified platelet-endothelial interactions and evaluated the contribution of major adhesion pathways.
  
  
  RESULTS
  Mice deficient for the low-density lipoprotein receptor and Apobec-1 were studied as an age-dependent model of atherosclerosis at 10, 20, 30, and 40 weeks of age, which provided progressive increase in stage from early fatty streak (10 weeks) to large complex plaques without rupture (40 weeks). Platelet-targeted contrast ultrasound molecular imaging of the thoracic aorta performed with microbubbles targeted to GPIbα demonstrated selective signal enhancement as early as 10 weeks of age. This signal increased progressively with age (almost 8-fold increase from 10 to 40 weeks, analysis of variance P<0.001). Specificity for platelet targeting was confirmed by the reduction in platelet-targeted signal commensurate with the decrease in platelet count after immunodepletion with anti-GPIb or anti-CD41 antibody. Inhibition of P-selectin in 20 and 40 weeks atherosclerotic mice resulted in a small (15% to 30%) reduction in platelet signal. Molecular imaging with microbubbles targeted to the A1 domain of von Willebrand factor demonstrated selective signal enhancement at all time points, which did not significantly increase with age. Treatment of 20 and 40 week mice with recombinant ADAMTS13 eliminated platelet and von Willebrand factor molecular imaging signal.
  
  
  CONCLUSIONS
  Platelet-endothelial interactions occur in early atherosclerosis. These interactions are in part caused by endothelial von Willebrand factor large multimers, which can be reversed with exogenous ADAMTS13.
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.).
authors.forename: Chi Young
authors.initials: CY
authors.lastname: Shim
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.).
authors.forename: Ya Ni
authors.initials: YN
authors.lastname: Liu
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.).
authors.forename: Tamara
authors.initials: T
authors.lastname: Atkinson
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.).
authors.forename: Aris
authors.initials: A
authors.lastname: Xie
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.).
authors.forename: Ted
authors.initials: T
authors.lastname: Foster
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.).
authors.forename: Brian P
authors.initials: BP
authors.lastname: Davidson
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.).
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Treible
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.).
authors.forename: Yue
authors.initials: Y
authors.lastname: Qi
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.).
authors.forename: José A
authors.initials: JA
authors.lastname: López
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.).
authors.forename: Adam
authors.initials: A
authors.lastname: Munday
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.).
authors.forename: Zaverio
authors.initials: Z
authors.lastname: Ruggeri
authors.affiliation: From the Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR (C.Y.S., Y.N.L., T.A., A.X., T.F., B.P.D., M.T., Y.Q., J.R.L.); Puget Sound Blood Center Research Institute, Seattle, WA (J.A.L., A.M.); and Department of Molecular and Experimental Medicine, Roon Research Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA (Z.R.). lindnerj@ohsu.edu.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lindner
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071120:ADAMTS13 Protein; D000071479:APOBEC-1 Deaminase; D000818:Animals; D001013:Aorta, Thoracic / Q000000981:diagnostic imaging / Q000378:metabolism*; D001018:Aortic Diseases / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000000981:diagnostic imaging / Q000378:metabolism*; D003287:Contrast Media; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000000981:diagnostic imaging / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D045423:Microbubbles; D008856:Microscopy, Fluorescence; D057054:Molecular Imaging / Q000379:methods*; D019007:P-Selectin / Q000378:metabolism; D010973:Platelet Adhesiveness; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D055503:Protein Multimerization; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D014463:Ultrasonography; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D003287:Contrast Media; D019007:P-Selectin; D019038:Platelet Glycoprotein GPIb-IX Complex; D011973:Receptors, LDL; C094990:adhesion receptor; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase
keywords: atherosclerosis; molecular imaging; platelet; von Willebrand factor