Molecular Ultrasound Imaging of Junctional Adhesion Molecule A Depicts Acute Alterations in Blood Flow and Early Endothelial Dysregulation

Adelina Curaj, Zhuojun Wu, Anne Rix, Oliver Gresch, Marieke Sternkopf, Setareh Alampour-Rajabi, Twan Lammers, Marc van Zandvoort, Christian Weber, Rory R. Koenen, Elisa A. Liehn, Fabian Kiessling*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 (approximate to 14x [P<0.001] and approximate to 5x [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.
Original languageEnglish
Pages (from-to)40-48
Number of pages9
JournalArteriosclerosis Thrombosis and Vascular Biology
Volume38
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • atherosclerosis
  • cell adhesion molecules
  • ligation
  • microbubbles
  • molecular imaging
  • SHEAR-STRESS
  • P-SELECTIN
  • WALL SHEAR
  • IN-VIVO
  • ATHEROSCLEROSIS
  • EXPRESSION
  • VCAM-1
  • MICROBUBBLES
  • CELLS
  • PLAQUE

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