Depletion of Endothelial-Derived 2-AG Reduces Blood-Endothelial Barrier Integrity via Alteration of VE-Cadherin and the Phospho-Proteome

Depletion of Endothelial-Derived 2-AG Reduces Blood-Endothelial Barrier Integrity via Alteration of VE-Cadherin and the Phospho-Proteome

Mounting evidence supports the role of the endocannabinoid system in neurophysiology, including blood-brain barrier (BBB) function. Recent work has demonstrated that activation of endocannabinoid receptors can mitigate insults to the BBB during neurological disorders like traumatic brain injury, cor...

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Bibliographic Details
Published in:International journal of molecular sciences Vol. 25; no. 1; p. 531
Main Authors: Levine, Aidan A, Liktor-Busa, Erika, Balasubramanian, Shreya, Palomino, Seph M, Burtman, Anya M, Couture, Sarah A, Lipinski, Austin A, Langlais, Paul R, Largent-Milnes, Tally M
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 30-12-2023
MDPI
Subjects:
2-AG
Antigens, CD
blood–brain barrier
Brain
Cadherins
Calcium
Calcium, Dietary
Cells
DAGLα
endocannabinoid
Endocannabinoids - pharmacology
Endothelial Cells
Endothelium
Ethical aspects
Homeostasis
Injuries
Instrument industry
Kinases
Lipids
Nervous system diseases
Neurophysiology
Protein kinases
Proteome
VE-cadherin
United States
Massachusetts
endocannabinoid
DAGLα
blood–brain barrier
2-AG
VE-cadherin
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Summary:Mounting evidence supports the role of the endocannabinoid system in neurophysiology, including blood-brain barrier (BBB) function. Recent work has demonstrated that activation of endocannabinoid receptors can mitigate insults to the BBB during neurological disorders like traumatic brain injury, cortical spreading depression, and stroke. As alterations to the BBB are associated with worsening clinical outcomes in these conditions, studies herein sought to examine the impact of endocannabinoid depletion on BBB integrity. Barrier integrity was investigated in vitro via bEnd.3 cell monolayers to assess endocannabinoid synthesis, barrier function, calcium influx, junctional protein expression, and proteome-wide changes. Inhibition of 2-AG synthesis using DAGLα inhibition and siRNA inhibition of DAGLα led to loss of barrier integrity via altered expression of VE-cadherin, which could be partially rescued by exogenous application of 2-AG. Moreover, the deleterious effects of DAGLα inhibition on BBB integrity showed both calcium and PKC (protein kinase C)-dependency. These data indicate that disruption of 2-AG homeostasis in brain endothelial cells, in the absence of insult, is sufficient to disrupt BBB integrity thus supporting the role of the endocannabinoid system in neurovascular disorders.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25010531