Trophoblast-derived extracellular vesicles elicit long-term effects on maternal cardiovascular function in a...

The hypertensive disease of pregnancy, preeclampsia, is a risk factor for future maternal cardiovascular disease while normal pregnancy is cardioprotective in the long term. Trophoblast-derived extracellular vesicles (T-EVs) released by the placenta are implicated in the development of vascular dysfunction and are widely thought to have a role in the pathogenesis of preeclampsia. This study tested the effects of T-EVs from both normotensive and preeclamptic pregnancies on long-term cardiovascular outcomes in a pregnant hypertensive model. Spontaneously hypertensive rats (SHRs) received intravenous vehicle control (CTEV; n = 11), and T-EVs from normotensive (NT; n = 10), early onset preeclamptic (EOPE; n = 10), or late-onset preeclamptic (LOPE; n = 10) pregnancies between days 8.5 and 18.5 of pregnancy (term = 22.5 days). SHRs were monitored during pregnancy and up to 12 mo postpartum, with noninvasive blood pressure plethysmography and echocardiography, followed by wire myography and histology. The NT group demonstrated significantly lower postpartum systolic blood pressure (SBP) compared with CTEV (P < 0.0001), whereas SBP in the EOPE group was increased (P < 0.0001). SBP was not significantly different between the CTEV and LOPE groups (P > 0.05). Terminal wire myography revealed that vessels from the NT group were more vasodilatory in response to acetylcholine (P = 0.0103) and less contractile in response to phenylephrine (P = 0.0435) and endothelin-1 (P < 0.0001). Vascular structure, cardiac function, and cardiac morphology were not different between all four T-EV groups. Exposure to T-EVs during pregnancy continued to influence maternal vascular function long after their administration. These findings confirm the role of T-EVs in regulating maternal vasculature long after the removal of the placenta at birth.NEW & NOTEWORTHY We have shown that normotensive T-EVs reduce blood pressure and promote a provasodilatory vascular phenotype for at least 12 mo after administration during pregnancy in a rat model. Administration of EOPE preeclamptic T-EVs prevented the natural decrease in blood pressure during pregnancy and increased blood pressure long-term. Together, these results suggest T-EVs play a key role in modulating maternal vascular function not only in pregnancy but also in determining future cardiovascular risk.