Endocannabinoid‐like N‐arachidonoyl serine is a novel pro‐angiogenic mediator

• Published in: British journal of pharmacology Vol. 160; no. 7; pp. 1583 - 1594
• Main Authors: Zhang, X, Maor, Y, Wang, JF, Kunos, G, Groopman, JE
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-08-2010; Nature Publishing Group
• Subjects: Angiogenesis; Animals; Antagonists; Arachidonic Acids - pharmacology; Biological and medical sciences; Cannabinoid CB1 receptors; Cannabinoid CB2 receptors; Cannabinoid Receptor Modulators - pharmacology; Capsaicin receptors; Cattle; Cell Line; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Chick Embryo; Chorioallantoic Membrane - blood supply; Chorioallantoic Membrane - drug effects; Dose-Response Relationship, Drug; Endocannabinoids; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; G protein-coupled receptors; G protein‐coupled receptor 55; Humans; Lipids; Medical sciences; Microvasculature; Neovascularization, Physiologic - drug effects; Pharmacology. Drug treatments; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - metabolism; Research Paper with; Serine; Serine - analogs & derivatives; Serine - pharmacology; Signal transduction; siRNA; Skin; transient receptor potential proteins; vascular endothelial growth factor C; Vasodilation; VEGF‐C; Wound healing; Wound Healing - drug effects; Endothelial cell; endothelial cells; wound healing; Arachidonic acid derivatives; Serine; G protein-coupled receptor 55; VEGF-C; Cannabinoid; Wound; Angiogenesis; Endogenous; Vascular endothelium growth factor; Endocannabinoid; Healing agent; G protein coupled receptor; Aminoacid; endocannabinoids
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/j.1476-5381.2010.00841.x

BACKGROUND AND PURPOSE N‐arachidonoyl serine (ARA‐S) is a recently identified endocannabinoid‐like lipid with weak affinity for the fully characterized cannabinoid receptors (CB1 and CB2) and the transient receptor potential vanilloid receptor 1 (TRPV‐1). ARA‐S induces vasodilatation and shows vasoprotective potential via activation of key signalling pathways in endothelial cells. Based on these findings, the effect of ARA‐S on endothelial functions was further studied.
EXPERIMENTAL APPROACH Primary human dermal microvascular endothelial cells (HMVEC) were used to investigate effects of ARA‐S (0‐10 µM) on certain endothelial functions, using cell proliferation, migration and wound repair models in vitro, and angiogenesis assays in vitro and ex vivo. Selective CB receptor antagonists and specific siRNAs were deployed to block individual CB receptors.
KEY RESULTS We found that ARA‐S stimulated angiogenesis and endothelial wound healing through induction of vascular endothelial growth factor C and its cognate receptor expression in primary HMVEC. Moreover, knock‐down of G protein‐coupled receptor 55 (GPR55) partly inhibited ARA‐S‐induced signal transduction and endothelial functions.
CONCLUSIONS AND IMPLICATIONS Our results indicate that ARA‐S is a pro‐angiogenic factor in addition to a vessel dilator. The GPR55 receptor may serve as one target of ARA‐S.