GPR55-mediated effects on brain microvascular endothelial cells and the blood–brain barrier

GPR55, an atypical cannabinoid receptor activated by lysophosphatidylinositol (LPI) has been involved in various physiological and pathological processes. We examined the effect of GPR55 activation on rat brain microvascular endothelial cells (RBMVEC), an essential component of the blood–brain barri...

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Published in:	Neuroscience Vol. 414; pp. 88 - 98
Main Authors:	Leo, Luciana M., Familusi, Boluwatife, Hoang, Michelle, Smith, Raymond, Lindenau, Kristen, Sporici, Kevin T., Brailoiu, Eugen, Abood, Mary E., Brailoiu, G. Cristina
Format:	Journal Article
Language:	English
Published:	United States Elsevier Ltd 21-08-2019
Subjects:	Animals Blood-Brain Barrier - drug effects Blood-Brain Barrier - metabolism blood–brain barrier Calcium - metabolism calcium signaling Calcium Signaling - drug effects Cell Line Dose-Response Relationship, Drug electrical resistance Endothelial Cells - drug effects Endothelial Cells - metabolism LPI Lysophospholipids - pharmacology Male Membrane Potentials - drug effects Microvessels - drug effects Microvessels - metabolism Rats Rats, Sprague-Dawley Receptors, Cannabinoid - metabolism Receptors, G-Protein-Coupled - metabolism BBB ZO-1 blood–brain barrier [Ca2+]i LPI RBMVEC PLC calcium signaling ECIS electrical resistance HBSS
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Summary:	GPR55, an atypical cannabinoid receptor activated by lysophosphatidylinositol (LPI) has been involved in various physiological and pathological processes. We examined the effect of GPR55 activation on rat brain microvascular endothelial cells (RBMVEC), an essential component of the blood–brain barrier (BBB). GPR55 was detected in RBMVEC by western blot and immunocytochemistry. Treatment of RBMVEC with LPI increased cytosolic Ca2+ concentration, [Ca2+]i, in a concentration-dependent manner; the effect was abolished by the GPR55 antagonist, ML-193. Repetitive application of LPI induced tachyphylaxis. LPI-induced increase in [Ca2+]i was not sensitive to U-73122, a phospholipase C inhibitor, but was abolished by the blockade of voltage-gated Ca2+ channels or in Ca2+-free saline, indicating that Ca2+ influx was involved in this response. LPI induced a biphasic change in RBMVEC membrane potential: a fast depolarization followed by a long-lasting hyperpolarization. The hyperpolarization phase was prevented by apamin and charibdotoxin, inhibitors of small- and intermediate-conductance Ca2+-activated K+ channels (KCa). Immunofluorescence studies indicate that LPI produced transient changes in tight and adherens junctions proteins and F-actin stress fibers. LPI decreased the electrical resistance of RBMVEC monolayer assessed with Electric Cell-Substrate Impedance Sensing (ECIS) in a dose-dependent manner. In vivo studies indicate that systemic administration of LPI increased the permeability of the BBB, assessed with Evans Blue method. Taken together, our results indicate that GPR55 activation modulates the function of endothelial cells of brain microvessels, produces a transient reduction in endothelial barrier function and increases BBB permeability. •GPR55, atypical cannabinoid receptor activated by LPI, is expressed in rat brain microvascular endothelial cells (RBMVEC).•In RBMVC, LPI increased cytosolic Ca2+ and produced a fast depolarization followed by a long-lasting hyperpolarization.•LPI disrupted tight and adherens junctions proteins and altered RBMVEC barrier function assessed with ECIS.•In vivo studies, reveal for the first time that LPI via GPR55 activation increases BBB permeability.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0306-4522 1873-7544
DOI:	10.1016/j.neuroscience.2019.06.039