Harhangi_2025_Hypertension_82_804

BACKGROUND: The endocannabinoid system (ECS) plays an important role in the early stages of pregnancy, while cannabis use during pregnancy associates with a greater risk of preeclampsia. This study quantified the placental ECS component mRNA levels in gestational age-matched healthy pregnant women, women with preeclampsia, and women who used cannabis throughout their pregnancy. Next, it compared the effects of the endogenous ECS agonists anandamide and 2-arachidonoylglycerol with those of the cannabinoid receptor type 1 and 2 agonists HU-210 and HU-308 in chorionic plate arteries. METHODS: Placental mRNA levels were quantified by quantitative polymerase chain reaction. Vascular reactivity was studied with and without selective cannabinoid receptor type 1 and 2 antagonists. RESULTS: mRNA levels of 1,2-diacylglycerol lipase alpha, responsible for 2-arachidonoylglycerol generation, were lowered in preeclampsia, while mRNA levels of the anandamide-synthesizing enzyme N-acyl phosphatidylethanolamine-specific phospholipase D were upregulated in cannabis users. Anandamide-induced relaxation in healthy pregnancy was mediated via cannabinoid receptors type 1 and 2, while 2-arachidonoylglycerol induced relaxation via cannabinoid receptor type 1. In preeclampsia, the effects of anandamide and 2-arachidonoylglycerol were unaltered but no longer involved cannabinoid receptors, while in cannabis users their effects were absent. HU-210 and HU-308 relaxed healthy, but not preeclamptic vessels. The NO donor sodium nitroprusside similarly relaxed healthy and preeclamptic vessels, while its effects in cannabis users were greatly reduced. CONCLUSIONS: The ECS is disturbed in preeclampsia, and endogenous ECS agonists lose their capacity to dilate in cannabis users, while such use also diminishes NO signaling. These data provide mechanistic evidence against cannabis use during pregnancy.