Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells

Mauro Maccarrone; Anna Fiori; Monica Bari; Filippo Granata; Valeria Gasperi; M. Egle De Stefano; Alessandro Finazzi-Agrò; Roberto Strom

doi:10.1160/TH05-06-0413

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(01): 117-127
DOI: 10.1160/TH05-06-0413

Endothelium and Vascular Development

Schattauer GmbH

Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells

Authors

Mauro Maccarrone

¹Department of Biomedical Sciences, University of Teramo, Italy

²IRCCS C. Mondino, Mondino-Tor Vergata Center for Experimental Neurobiology, Rome, Italy
Anna Fiori

³Departments of Biochemical Sciences “A. Rossi Fanelli”, University of Rome La Sapienza, Italy
Monica Bari

¹Department of Biomedical Sciences, University of Teramo, Italy
Filippo Granata

⁴Departments of Cellular and Developmental Biology, University of Rome La Sapienza, Italy
Valeria Gasperi

⁵Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy
M. Egle De Stefano

⁴Departments of Cellular and Developmental Biology, University of Rome La Sapienza, Italy
Alessandro Finazzi-Agrò

⁵Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy
Roberto Strom

⁶Departments of Cellular Biotechnology and Hematology, University of Rome La Sapienza, Italy

Abstract

Summary

The endocannabinoid anandamide (AEA) has many neurovascular activities. However, it is not yet clear how AEA can be metabolized at the neurovascular interface, and how it can move through the vascular and the cerebral compartments. The results reported in this article show that isolated bovine brain microvessels, an ex vivo model of the blood-brain barrier, have detectable levels of endogenous AEA and possess the biochemical machinery to bind and metabolize it, i. e. type-1 and type-2 cannabinoid receptors (CB1R and CB2R), a selective AEA membrane transporter (AMT), an AEA-degrading fatty acid amide hydrolase, and the AEA-synthesizing enzymes N-acyltransferase and N-acyl-phosphatidylethanolamines-specific phospholipase D. We also show that activation of CB1R enhances AMT activity through increased nitric oxide synthase (NOS) activity and subsequent increase of NO production. AMT activity is instead reduced by activation of CB2R, which inhibits NOS and NO release. In addition, binding experiments and immunoelectronmicroscopy demonstrate that different endothelial cells vary in the expression of CB1R and CB2R on the luminal and/or abluminal sides. The different localization of CBRs can lead to a diverse effect on AMT activity on the luminal and abluminal membranes, suggesting that the distribution of these receptors may drive AEA directional transport through the blood-brain barrier and other endothelial cells.

Keywords

Brain - directional uptake - endocannabinoids - endothelial cells - nitric oxide - receptors - transporters

Full Text

References

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