Placental extracellular vesicles from early-onset but not late-onset preeclampsia induce a pro-vasoconstrictive and anti-vasodilatory state in resistance arteries

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Abstract
Background: The human placenta releases large numbers of extracellular vesicles (EVs) into the maternal circulation throughout pregnancy. In preeclampsia, a hypertensive disorder of pregnancy, the number of EVs increases and the cargo they carry is altered. We investigated whether human placental EVs from pregnancies complicated by preeclampsia directly alter maternal vascular function, a hallmark of the disorder, and if EVs from early-onset or late-onset variants of preeclampsia have different effects on the vasculature. Methods: Macro-EVs, micro-EVs and nano-EVs were isolated from cultured explants of human placentae from women with early-onset or late-onset preeclampsia, or from normotensive women. EVs were injected intravenously into pregnant mice and either at 30 minutes or 24 hours after injection, the mice were euthanized and the function of second order mesenteric arteries were assessed using wire myography. Results: Placental EVs from pregnancies with early-onset preeclampsia enhanced vasoconstriction to PE, AngII, and ET-1 whilst impairing vasodilation to ACh and SNP in a time-dependent fashion, most prominently at 24 hours. In contrast, placental EVs from pregnancies with late-onset preeclampsia induced few differences compared to arteries taken from control mice injected with EVs from women with normotensive pregnancies. Conclusions: To the best of our knowledge, this is the first comparison of vascular function after exposure to the full range of EVs produced by placentae from women with early-onset and late-onset preeclampsia and normotensive women. Placental EVs from early-onset preeclampsia demonstrated the ability to contribute to the development of the high-resistance haemodynamic profiles of women affected by early-onset preeclampsia.

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