Adelina Curaj1, Zhuojun Wu1, Anne Rix1, Oliver Gresch1, Marieke Sternkopf1, Setareh Alampour-Rajabi1, Twan Lammers1, Marc van Zandvoort1, Christian Weber1, Rory R Koenen1, Elisa A Liehn1, Fabian Kiessling2. 1. From the Institute for Molecular Cardiovascular Research (IMCAR) (A.C., Z.W., M.S., S.A.-R., M.v.Z., E.A.L.), and Institute for Experimental Molecular Imaging (ExMI) (A.C., Z.W., A.R., T.L., F.K.), University Hospital Aachen, RWTH Aachen, Germany; Victor Babes National Institute of Pathology, Bucharest, Romania (A.C.); AYOXXA Biosystems GmbH, Cologne, Germany (O.G.); Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands (T.L.); Department of Genetics and Molecular Cell Biology, School for Oncology and Developmental Biology (GROW), Maastricht University, The Netherlands (M.v.Z., R.R.K.); Department of Biochemistry, School for Cardiovascular Diseases (CARIM), Maastricht University, The Netherlands (M.v.Z., C.W.); German Centre for Cardiovascular Research, partner site Munich Heart Alliance (DZHK), Germany (C.W.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany (C.W.); and Human Genetic Laboratory, University for Medicine and Pharmacy, Craiova, Romania (E.A.L.). 2. From the Institute for Molecular Cardiovascular Research (IMCAR) (A.C., Z.W., M.S., S.A.-R., M.v.Z., E.A.L.), and Institute for Experimental Molecular Imaging (ExMI) (A.C., Z.W., A.R., T.L., F.K.), University Hospital Aachen, RWTH Aachen, Germany; Victor Babes National Institute of Pathology, Bucharest, Romania (A.C.); AYOXXA Biosystems GmbH, Cologne, Germany (O.G.); Department of Targeted Therapeutics, University of Twente, Enschede, The Netherlands (T.L.); Department of Genetics and Molecular Cell Biology, School for Oncology and Developmental Biology (GROW), Maastricht University, The Netherlands (M.v.Z., R.R.K.); Department of Biochemistry, School for Cardiovascular Diseases (CARIM), Maastricht University, The Netherlands (M.v.Z., C.W.); German Centre for Cardiovascular Research, partner site Munich Heart Alliance (DZHK), Germany (C.W.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany (C.W.); and Human Genetic Laboratory, University for Medicine and Pharmacy, Craiova, Romania (E.A.L.). fkiessling@ukaachen.de.
Abstract
OBJECTIVE: The junctional adhesion molecule A (JAM-A) is physiologically located in interendothelial tight junctions and focally redistributes to the luminal surface of blood vessels under abnormal shear and flow conditions accompanying atherosclerotic lesion development. Therefore, JAM-A was evaluated as a target for molecularly targeted ultrasound imaging of transient endothelial dysfunction under acute blood flow variations. APPROACH AND RESULTS: Flow-dependent endothelial dysfunction was induced in apolipoprotein E-deficient mice (n=43) by carotid partial ligation. JAM-A expression was investigated by molecular ultrasound using antibody-targeted poly(n-butyl cyanoacrylate) microbubbles and validated with immunofluorescence. Flow disturbance and arterial remodeling were assessed using functional ultrasound. Partial ligation led to an immediate drop in perfusion at the ligated side and a direct compensatory increase at the contralateral side. This was accompanied by a strongly increased JAM-A expression and JAM-A-targeted microbubbles binding at the partially ligated side and by a moderate and temporary increase in the contralateral artery (≈14× [P<0.001] and ≈5× [P<0.001] higher than control, respectively), both peaking after 2 weeks. Subsequently, although JAM-A expression and JAM-A-targeted microbubbles binding persisted at a higher level at the partially ligated side, it completely normalized within 4 weeks at the contralateral side. CONCLUSIONS: Temporary blood flow variations induce endothelial rearrangement of JAM-A, which can be visualized using JAM-A-targeted microbubbles. Thus, JAM-A may be considered as a marker of acute endothelial activation and dysfunction. Its imaging may facilitate the early detection of cardiovascular risk areas, and it enables the therapeutic prevention of their progression toward an irreversible pathological state.
OBJECTIVE: The junctional adhesion molecule A (JAM-A) is physiologically located in interendothelial tight junctions and focally redistributes to the luminal surface of blood vessels under abnormal shear and flow conditions accompanying atherosclerotic lesion development. Therefore, JAM-A was evaluated as a target for molecularly targeted ultrasound imaging of transient endothelial dysfunction under acute blood flow variations. APPROACH AND RESULTS: Flow-dependent endothelial dysfunction was induced in apolipoprotein E-deficientmice (n=43) by carotid partial ligation. JAM-A expression was investigated by molecular ultrasound using antibody-targeted poly(n-butyl cyanoacrylate) microbubbles and validated with immunofluorescence. Flow disturbance and arterial remodeling were assessed using functional ultrasound. Partial ligation led to an immediate drop in perfusion at the ligated side and a direct compensatory increase at the contralateral side. This was accompanied by a strongly increased JAM-A expression and JAM-A-targeted microbubbles binding at the partially ligated side and by a moderate and temporary increase in the contralateral artery (≈14× [P<0.001] and ≈5× [P<0.001] higher than control, respectively), both peaking after 2 weeks. Subsequently, although JAM-A expression and JAM-A-targeted microbubbles binding persisted at a higher level at the partially ligated side, it completely normalized within 4 weeks at the contralateral side. CONCLUSIONS: Temporary blood flow variations induce endothelial rearrangement of JAM-A, which can be visualized using JAM-A-targeted microbubbles. Thus, JAM-A may be considered as a marker of acute endothelial activation and dysfunction. Its imaging may facilitate the early detection of cardiovascular risk areas, and it enables the therapeutic prevention of their progression toward an irreversible pathological state.
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2019-12-23 Impact factor: 8.311
Authors: Elke Bouwens; Victor J van den Berg; K Martijn Akkerhuis; Sara J Baart; Kadir Caliskan; Jasper J Brugts; Henk Mouthaan; Jan van Ramshorst; Tjeerd Germans; Victor A W M Umans; Eric Boersma; Isabella Kardys Journal: J Clin Med Date: 2020-01-10 Impact factor: 4.241