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Role of sphingolipids in fibrinogen‐induced cerebrovascular permeability
Author(s) -
Muradashvili Nino,
Khundmiri Syed Jalal,
Tyagi Reeta,
Lee MenqJer,
Lominadze David
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1131.9
Subject(s) - sphingolipid , paracellular transport , transcellular , vascular permeability , albumin , chemistry , permeability (electromagnetism) , blood–brain barrier , inflammation , cholesterol , fibrinogen , biophysics , microbiology and biotechnology , biochemistry , biology , endocrinology , immunology , membrane , central nervous system
We showed that at an elevated level fibrinogen (Fg), a marker of inflammation, compromises endothelial cell (EC) layer integrity and increases cerebrovascular permeability. Since we found that Fg increases level of sphingolipids in mouse brain ECs (MBECs), we tested the role of cholesterol and sphingolipids in Fg‐induced permeability of MBECs. Role of cholesterol and sphingolipids in Fg‐induced albumin crossing of MBECs layer was evaluated with a dual‐tracer probing method (allows differentiation of paracellular and transcellular transports). We found that chelation of cholesterol by methyl‐beta‐cyclodextrin (MβCD) inhibited leakage of both low molecular weight (LMW) and high molecular weight (HMW) tracers through EC layer. However, inhibition of sphingolipid de‐novo synthesis by myriocin inhibited Fg‐induced overall leakage (assessed by crossing of HMW tracer through MBECs), but did not affect leakage of LMW tracer. In addition, myriocin inhibited cerebrovascular leakage of albumin in mice with elevated blood level of Fg. The present study suggests that at high level Fg increases cerebrovascular permeability altering mainly the transendothelial transport by enhancing formation of functional caveolae via sphingolipid signaling. Thus, sphingolipids can be identified as new targets for therapeutic intervention that can modulate inflammation‐induced cerebrovascular permeability