title: Noninvasive molecular ultrasound monitoring of vessel healing after intravascular surgical procedures in a preclinical setup.
abstract: OBJECTIVE
  Cardiovascular interventions induce damage to the vessel wall making antithrombotic therapy inevitable until complete endothelial recovery. Without a method to accurately determine the endothelial status, many patients undergo prolonged anticoagulation therapy, denying them any invasive medical procedures, such as surgical operations and dental interventions. Therefore, we aim to introduce molecular ultrasound imaging of the vascular cell adhesion molecule (VCAM)-1 using targeted poly-n-butylcyanoacrylate microbubbles (MB(VCAM-1)) as an easy accessible method to monitor accurately the reendothelialization of vessels.
  
  
  RESULTS
  ApoE(-/-) mice were fed with an atherogenic diet for 1 and 12 weeks and subsequently, endothelial denudation was performed in the carotid arteries using a guidewire. Molecular ultrasound imaging was performed at different time points after denudation (1, 3, 7, and 14 days). An increased MB(VCAM-1) binding after 1 day, a peak after 3 days, and a decrease after 7 days was found. After 12 weeks of diet, MB(VCAM-1) binding also peaked after 3 days but remained high until 7 days, indicating a delay in endothelial recovery. Two-photon laser scanning microscopy imaging of double fluorescence staining confirmed the exposure of VCAM-1 on the superficial layer after arterial injury only during the healing phase. After complete reendothelialization, VCAM-1 expression persisted in the subendothelial layer but was not reachable for the MBV(CAM-1) anymore.
  
  
  CONCLUSIONS
  Molecular ultrasound imaging with MB(VCAM-1) is promising to assess vascular damage and to monitor endothelial recovery after arterial interventions. Thus, it may become an important diagnostic tool supporting the development of adequate therapeutic strategies to personalize anticoagulant and anti-inflammatory therapy after cardiovascular intervention.
authors.affiliation: From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.).
authors.forename: Adelina
authors.initials: A
authors.lastname: Curaj
authors.affiliation: From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.).
authors.forename: Zhuojun
authors.initials: Z
authors.lastname: Wu
authors.affiliation: From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.).
authors.forename: Stanley
authors.initials: S
authors.lastname: Fokong
authors.affiliation: From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.).
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Liehn
authors.affiliation: From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.).
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.).
authors.forename: Alexandrina
authors.initials: A
authors.lastname: Burlacu
authors.affiliation: From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.).
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
authors.affiliation: From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.). fkiessling@ukaachen.de mamj.vanzandvoort@maastrichtuniversity.nl.
authors.forename: Marc
authors.initials: M
authors.lastname: van Zandvoort
authors.affiliation: From the Institute for Experimental Molecular Imaging (A.C., Z.W., S.F., T.L., F.K.), Institute for Molecular Cardiovascular Research (A.C., Z.W., E.A.L., M.v.Z.), University Clinic, RWTH Aachen University, Aachen, Germany; Institute of Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Alliance), Munich, Germany (C.W.); Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, Bucharest, Romania (A.B.); Department of Controlled Drug Delivery, University of Twente, AE Enschede, The Netherlands (T.L.); and Department of Genetics and Molecular Cell Biology, School for Cardiovascular Diseases CARIM, Maastricht University, Maastricht, The Netherlands (M.v.Z.). fkiessling@ukaachen.de mamj.vanzandvoort@maastrichtuniversity.nl.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000601:surgery*; D015415:Biomarkers / Q000378:metabolism; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000473:pathology / Q000601:surgery; D004195:Disease Models, Animal; D004659:Enbucrilate; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging* / Q000293:injuries / Q000473:pathology / Q000601:surgery*; D057510:Endovascular Procedures; D051379:Mice; D045423:Microbubbles; D018613:Microscopy, Confocal; D014463:Ultrasonography; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D014945:Wound Healing
chemical_list: D015415:Biomarkers; D019010:Vascular Cell Adhesion Molecule-1; D004659:Enbucrilate
keywords: atherosclerosis; microbubbles; molecular imaging; ultrasonography