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      Sphingolipids affect fibrinogen-induced caveolar transcytosis and cerebrovascular permeability.

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          Abstract

          Inflammation-induced vascular endothelial dysfunction can allow plasma proteins to cross the vascular wall, causing edema. Proteins may traverse the vascular wall through two main pathways, the paracellular and transcellular transport pathways. Paracellular transport involves changes in endothelial cell junction proteins, while transcellular transport involves caveolar transcytosis. Since both processes are associated with filamentous actin formation, the two pathways are interconnected. Therefore, it is difficult to differentiate the prevailing role of one or the other pathway during various pathologies causing an increase in vascular permeability. Using a newly developed dual-tracer probing method, we differentiated transcellular from paracellular transport during hyperfibrinogenemia (HFg), an increase in fibrinogen (Fg) content. Roles of cholesterol and sphingolipids in formation of functional caveolae were assessed using a cholesterol chelator, methyl-β-cyclodextrin, and the de novo sphingolipid synthesis inhibitor myriocin. Fg-induced formation of functional caveolae was defined by association and colocalization of Na+-K+-ATPase and plasmalemmal vesicle-associated protein-1 with use of Förster resonance energy transfer and total internal reflection fluorescence microscopy, respectively. HFg increased permeability of the endothelial cell layer mainly through the transcellular pathway. While MβCD blocked Fg-increased transcellular and paracellular transport, myriocin affected only transcellular transport. Less pial venular leakage of albumin was observed in myriocin-treated HFg mice. HFg induced greater formation of functional caveolae, as indicated by colocalization of Na+-K+-ATPase with plasmalemmal vesicle-associated protein-1 by Förster resonance energy transfer and total internal reflection fluorescence microscopy. Our results suggest that elevated blood levels of Fg alter cerebrovascular permeability mainly by affecting caveolae-mediated transcytosis through modulation of de novo sphingolipid synthesis.

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          Author and article information

          Journal
          Am. J. Physiol., Cell Physiol.
          American journal of physiology. Cell physiology
          American Physiological Society
          1522-1563
          0363-6143
          Jul 15 2014
          : 307
          : 2
          Affiliations
          [1 ] Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, Kentucky;
          [2 ] Kidney Disease Program, Department of Medicine, School of Medicine, University of Louisville, Louisville, Kentucky;
          [3 ] Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan.
          [4 ] Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, Louisville, Kentucky; and.
          [5 ] Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, Kentucky; david.lominadze@louisville.edu.
          Article
          ajpcell.00305.2013
          10.1152/ajpcell.00305.2013
          4101621
          24829496
          069ffda1-afc4-4777-8ca0-467deb87215a
          History

          protein leakage,total internal reflection fluorescence microscopy,functional caveolae,cholesterol,Förster resonance energy transfer microscopy

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