Neonatal MicroRNA Profile Determines Endothelial Function in Offspring of Hypertensive Pregnancies

Abstract

Offspring of hypertensive pregnancies are at increased risk of developing hypertension in adulthood. In the neonatal period they display endothelial cell dysfunction and altered microvascular development. MicroRNAs, as important endothelial cellular regulators, may play a role in this early endothelial dysfunction. Therefore we identified differential microRNA patterns in endothelial cells from offspring of hypertensive pregnancies and determined their role in postnatal vascular cell function. Studies were performed on human umbilical vein endothelial cell (HUVECs) samples from 57 pregnancies. Unbiased RNA-sequencing identified 30 endothelial-related microRNAs differentially expressed in HUVECs from hypertensive compared to normotensive pregnancies. Quantitative reverse transcription PCR (RT-qPCR) confirmed a significant higher expression level of the top candidate, miR-146a. Combined miR-146a targeted gene expression and pathway analysis revealed significant alterations in genes involved in inflammation, angiogenesis and immune response in the same HUVECs. Elevated miR-146a expression level at birth identified cells with reduced ability for in vitro vascular tube formation, which was rescued by miR-146a inhibition. In contrast, miR-146a overexpression significantly reduced vascular tube formation in HUVECs from normotensive pregnancies. Finally, we confirmed that mir146a levels at birth predicted in vivo microvascular development during the first three postnatal months. Offspring of hypertensive pregnancy have a distinct endothelial regulatory microRNA profile at birth, which is related to altered endothelial cell behaviour, and predicts patterns of microvascular development during the first three months of life. Modification of this microRNA profile in vitro can restore impaired vascular cell function.

Preeclampsia: Risk Factors, Diagnosis, Management, and the Cardiovascular Impact on the Offspring

“…While the precise mechanisms are yet to be fully elucidated, potential mediators for the abnormalities in vascular development in the offspring of preeclamptic pregnancies include derangement of maternal angiogenic factors, inherited polymorphisms, epigenetic factors, and altered microRNA expression [154,159,160]. Yu et al [159] analysed the maternal angiogenic profile alongside assessments of neonatal endothelial cells at birth, and vascular density in the offspring at three months postpartum in hypertensive and normotensive pregnancies.…”

“…This disruption of microvascular development was proportional to peripartum levels of maternal sFlt-1, implicating a role for maternal angiogenic factors in the abnormal development of the foetal vasculature in hypertensive pregnancies [159]. The neonatal microRNA profile also appears to play a role in mediating endothelial changes in the offspring of hypertensive pregnancies [160]. In particular, a specific microRNA involved in endothelial gene regulation, miR-146a, was shown to differ significantly between offspring of normotensive and hypertensive pregnancies, with direct correlations to HUVEC proliferation capacity and tube formation.…”

The Transitional Heart: From Early Embryonic and Fetal Development to Neonatal Life

“…Exposure to a hypoxic intrauterine environment is associated with offspring vascular, metabolic, and cardiac modifications including aortic wall thickening, loss of NO vessel modulation, altered LV function, and increased susceptibility to ischemia and metabolic syndrome [110][111][112]. Recently, it has become apparent that offspring of hypertensive pregnancies may also have microvascular genotypic and phenotypic abnormalities that may persist beyond the perinatal period and into adulthood [113][114][115][116], which may account for their significantly lower threshold for the development of cardiovascular-related diseases [110]. While studies assessing the specific impact of preeclampsia on cardiac remodeling during the transition from fetal to neonatal life remain limited, further investigations are needed given that adolescents and young adults who were exposed to maternal preeclampsia display unique LV remodeling patterns including greater relative wall thickness, smaller internal cavity diameter, and lower longitudinal peak systolic strain [112,117].…”

The Role of Epigenetics in Placental Development and the Etiology of Preeclampsia

“…The study of the role that miRs may have in the different cell types present in the placenta is indispensable to understand the role of this molecules in the development of the disease. In the long term, it has also been shown that miRNA profiles in the neonate is altered following an hypertensive pregnancy; for instance the level of mir-146a at birth predict microvascular development three months later [262].…”