THE PLACENTAL ENDOCANNABINOID SYSTEM IN HEALTHY AND PREECLAMPTIC WOMEN: CONSEQUENCE OF CANNABIS USE DURING PREGNANCY

Objective: The endocannabinoid system (ECS) plays an important role in the early stages of pregnancy, while cannabis use during pregnancy associates with preeclampsia. This study first quantified the placental expression of ECS components in gestational age-matched healthy pregnant women, women with early-onset preeclampsia (eoPE), and women who used cannabis throughout their pregnancy. Secondly, it studied the effects of the endogenous ECS agonists anandamide and 2-aragydonoylglycerol in chorionic plate arteries of these women. Design and method: Expression was quantified by qPCR, while vessel reactivity was studied in organ baths, also making use of cannabinoid receptor type 1 and 2 antagonists. Results: The expression of 1,2-diacylglycerol lipase α, responsible for 2-aragydonoylglycerol generation, was lowered in eoPE, while the expression of the anandamide-synthesizing enzyme N-acyl phosphatidylethanolamine-specific phospholipase D was upregulated in cannabis users. Anandamide-induced relaxation in healthy pregnancy was mediated via cannabinoid receptors type 1 and 2, while 2-aragydonoylglycerol induced relaxation via cannabinoid receptor type 1. In eoPE, the effects of the eCBs were unaltered, but no longer involved cannabinoid receptors, while in cannabis users their effects were virtually absent. The selective cannabinoid receptor type 1 and 2 agonists HU-210 and HU-308 relaxed healthy, but not eoPE vessels. The NO donor sodium nitroprusside relaxed healthy and eoPE vessels to the same degree, while its effects in cannabis users were greatly reduced. Conclusions: The ECS is disturbed in eoPE, and endogenous ECS agonists lose their capacity to dilate in cannabis users, while such use also diminishes NO signaling. These data this data provide further mechanistic evidence against cannabis use during pregnancy.