Endothelial cannabinoid CB1 receptor deficiency reduces shear stress-induced arterial inflammation and lipid uptake
Abstract
Abstract Peripheral cannabinoid CB1 receptor antagonists that lack central nervous system effects are emerging as promising therapies for metabolic disease, yet the role of endothelial CB1 signaling in atherosclerosis remains unclear. Here, we show that endothelial CB1 is expressed in human atherosclerotic plaques, is induced by oscillatory shear stress in atheroprone flow regions, and promotes vascular inflammation, permeability and lipid uptake. Endothelial-specific Cnr1 deletion or peripheral CB1 antagonism in mice attenuates atherosclerosis, reduces endothelial caveolae–dependent low-density lipoprotein uptake by downregulating caveolin-1 and ALK1 expression, and improves metabolic parameters in brown and white adipose tissue and the liver. The anti-atherogenic and metabolic effects are more pronounced in females, which is possibly linked to estrogen signaling. These findings identify endothelial CB1 as a proatherogenic, sex-biased regulator of vascular lipid transport and plaque development and associated metabolic dysfunction.
Article Details
Authors (29)
Bingni Chen
Aishvaryaa Prabhu
Guo Li
Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University
Anna Kaltenbach
Yong Wang
George Shakir
Lucia Natarelli
Remco Megens
Yvonne Jansen
Srishti Ramanathan
Martina Geiger
Alexander Faussner
Michael Hristov
Daniel Richter
Xinyu Di
Mario van der Stelt
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research
Vasiliki Triantafyllidou
Zhaolong Li
Nadja Sachs
Valentina Paloschi
Lars Maegdefessel
Susanna M. Hofmann
Martina Schifferer
Mikael Simons
Christian Weber
Donato Santovito
Stephan Herzig
Raquel Guillamat Prats
Sabine Steffens