The effects of first-trimester placental extracellular vesicles on maternal vascular tone

Abstract

Introduction: Maternal cardiovascular adaptations are essential for a successful pregnancy and are characterised by a large decrease in systemic vascular resistance, complementing the increases in cardiac output and blood volume. Both maternal and placental factors are thought to contribute to these changes. Throughout gestation, placental extracellular vesicles (EVs) are extruded directly into the maternal circulation, and EVs are known mediators of cell communication. The anatomy of the placenta allows three types of EVs to be extruded, classified by their size (macro-, micro-, and nanovesicles). We hypothesised that first-trimester human placental EVs contribute to the decrease in systemic vascular resistance that occurs in the first-trimester of pregnancy. Aims: 1. To systematically review the current literature on the effects of EVs on vascular tone. 2. To determine the effects of first-trimester placental EVs on maternal vascular responses to vasoactive stimuli and whether the effect is time-dependent. Methods: Placental EVs were isolated from the conditioned media of first-trimester placental explants via differential centrifugation to obtain each type of EV. Placental EVs were administered into time-mated pregnant mice via tail-vein injection, and after 30-minutes or 24 hours, mesenteric arteries were collected for the wire myography experiments. Dose-response curves to vasoconstrictors (phenylephrine, angiotensin II and endothelin-1) and vasodilators (acetylcholine and sodium nitroprusside) were generated from the wire myography experiments. Results: A systematic review of the literature demonstrated that EVs could affect vascular tone regardless of the origin of the EVs and the recipient species. In agreement, all three types of placental EVs can affect the vessel responsiveness to vasoconstrictors and vasodilators after 30-minutes and 24 hours of exposure. Placental EVs had time-dependent effects, appearing pro-constrictive and anti-dilatory at 30-minutes, whereas, after 24 hours, the effect was anticonstrictive and pro-dilatory. Discussion: First-trimester placental EVs can induce anti-constrictive and pro-dilatory effects after 24 hours of exposure, consistent with the decrease in systemic vascular resistance seen in the first-trimester of pregnancy. The time-dependent nature suggests that these effects are not immediate but develop within the vasculature over time. Placental EVs may be one of the contributors to maternal cardiovascular changes during normal pregnancy.