Endothelial cannabinoid CB1 receptor deficiency reduces arterial inflammation and lipid uptake in response to atheroprone shear stress

Endothelial cannabinoid CB1 receptor deficiency reduces arterial inflammation and lipid uptake in response to atheroprone shear stress | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Endothelial cannabinoid CB1 receptor deficiency reduces arterial inflammation and lipid uptake in response to atheroprone shear stress Sabine Steffens, Bingni Chen, Aishvaryaa Prabhu, Guo Li, Anna Kaltenbach, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6944788/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Peripherally restricted cannabinoid CB1 receptor antagonists without central side effects hold promise for treating metabolic disorders including diabetes and obesity. In atherosclerosis, the specific effects of peripheral endothelial CB1 signaling remain incompletely understood. Here, we report the expression of the CB1 encoding gene CNR1 in arterial endothelial cells of human plaques. We also show that endothelial CNR1 expression is increased by oscillatory shear stress (OSS) in human aortic endothelial cells (HAoECs) and is higher in atheroprone regions than in atheroresistant regions of murine aortas. Endothelial CB1 deficiency (Cnr1EC-KO) in atheroprone mice resulted in pronounced endothelial phenotypic changes with reduced vascular inflammation and permeability. This led to reduced plaque development with a lower lipid content in female mice, whereas attenuated plaque development, but no changes in plaque lipid content were found in males. Reduced white and brown adipose tissue mass and liver steatosis upon Cnr1EC-KO were observed in both males and females. Ex vivo imaging of female carotid arteries revealed less low density lipoprotein (Dil-LDL) uptake in Cnr1EC-KO. This was accompanied by reduced endothelial caveolin-1 (CAV1) expression, a key structural protein involved in lipid transcytosis, which was only observed in female Cnr1EC-KO mice. In vitro, pharmacological blocking with CB1 antagonist AM281 reproduced the inhibition of CAV1 expression and Dil-LDL uptake in response to atheroprone OSS in HAoECs, which was dependent on cAMP-mediated PKA activation. Conversely, the CB1 agonist ACEA increased Dil-LDL uptake and CAV1 expression in HAoECs. Chronic treatment of atherosclerotic mice with the peripheral CB1 antagonist JD-5037 reduced plaque progression and endothelial CAV1 expression in female mice. Consistent with more pronounced effects in females, HAECs treated with the estrogen receptor ligand estradiol exhibited increased CNR1 and CAV1 expression. These results support a proatherogenic role of endothelial CB1, which appears to be more pronounced in females. Health sciences/Cardiology/Cardiovascular biology/Cardiovascular diseases/Vascular diseases/Atherosclerosis Health sciences/Medical research/Experimental models of disease Health sciences/Molecular medicine cannabinoid CB1 receptor shear stress endothelial cells caveolin LDL transport Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6944788","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":509301738,"identity":"a2f8289c-38cd-48b9-aa35-bfbaf83d2df3","order_by":0,"name":"Sabine 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In atherosclerosis, the specific effects of peripheral endothelial CB1 signaling remain incompletely understood. Here, we report the expression of the CB1 encoding gene CNR1 in arterial endothelial cells of human plaques. We also show that endothelial CNR1 expression is increased by oscillatory shear stress (OSS) in human aortic endothelial cells (HAoECs) and is higher in atheroprone regions than in atheroresistant regions of murine aortas. Endothelial CB1 deficiency (Cnr1EC-KO) in atheroprone mice resulted in pronounced endothelial phenotypic changes with reduced vascular inflammation and permeability. This led to reduced plaque development with a lower lipid content in female mice, whereas attenuated plaque development, but no changes in plaque lipid content were found in males. Reduced white and brown adipose tissue mass and liver steatosis upon Cnr1EC-KO were observed in both males and females. Ex vivo imaging of female carotid arteries revealed less low density lipoprotein (Dil-LDL) uptake in Cnr1EC-KO. This was accompanied by reduced endothelial caveolin-1 (CAV1) expression, a key structural protein involved in lipid transcytosis, which was only observed in female Cnr1EC-KO mice. In vitro, pharmacological blocking with CB1 antagonist AM281 reproduced the inhibition of CAV1 expression and Dil-LDL uptake in response to atheroprone OSS in HAoECs, which was dependent on cAMP-mediated PKA activation. Conversely, the CB1 agonist ACEA increased Dil-LDL uptake and CAV1 expression in HAoECs. Chronic treatment of atherosclerotic mice with the peripheral CB1 antagonist JD-5037 reduced plaque progression and endothelial CAV1 expression in female mice. Consistent with more pronounced effects in females, HAECs treated with the estrogen receptor ligand estradiol exhibited increased CNR1 and CAV1 expression. 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