Contrasting cannabinoid receptor 2 (CB2R)-mediated responses in two different models of Blood Brain Barrier in the context of HIV

The infection with the Human Immunodeficiency Virus is associated with several comorbidities despite suppressive antiretrovirals, which include consequences to the Central Nervous System (CNS), where disruption of the blood-brain barrier (BBB) a major underlying factor in the resulting chronic inflammation and pathogenesis. Currently, the use of cannabis and cannabinoid derivatives among persons living with HIV (PWH) is common. Despite perceived benefits, we have previously identified context-dependent effects of cannabis use, including in vascular biomarkers. In this study, we used an in vitro multicellular BBB model with two different human stable cerebrovascular endothelial cell lines (hCMEC/D3 and HBMEC/ci18) to test the effects of cannabinoids via their receptors on integrity and function in the context of exposure to conditioned media from HIV latently infected promonocytes. We found that the two cell lines had similar responses to HIV-conditioned media by increasing permeability to dextran and decreasing tight junction proteins. However, their response to cannabinoids, particularly via the cannabinoid receptor 2 (CB2R) was markedly contrasting, with hCMEC/D3 cells showing improvement of BBB integrity by all measures, and HBMEC/ci18 cells showing no benefits or aggravation of damage. While the contrasting effects were not due to differences in viability or proliferation, GPCR response with production of cAMP was above 50-fold higher in hCMEC/D3 cells, including at baseline, in correlation with higher availability of CB2R compared to HBMEC/ci18. Our study suggests that CB2R levels and activation threshold on cerebrovascular endothelium may dictate improvements versus aggravating effects of cannabis to the BBB of PWH.