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Human umbilical venous endothelial cells (HUVECs) have long been utilized as an in vitro model for study of endothelial cell function and their response to different stimuli. In 2017, Brodowski et al reported that preeclampsia altered endothelial function in HUVECs. It is well established that preeclampsia is not only associated with an increased incidence of maternal and fetal morbidity and mortality but also greater cardiovascular disease in the offspring. Thus, Brodowski et al hypothesized that reduced functional ability in HUVECs from pregnancies complicated by preeclampsia predicted greater cardiovascular risk in offspring. In this issue of Hypertension, Zhou et al extend this hypothesis to determine whether fetal sex alters HUVEC function and to provide insight into potential mechanisms responsible for sex differences in increased cardiovascular risk in offspring of pregnancies complicated by preeclampsia. Using unpassaged HUVECs isolated from normotensive (>39 weeks of gestation) and preeclamptic pregnancies (>37 of weeks gestation) coupled to RNA sequencing analysis, Zhou et al tested the hypothesis that preeclampsia results in sex-specific changes in cardiovascular disease–associated and endothelial function–associated gene pathways. They found that sex differences in genetic variants were particularly significant in HUVECs from preeclamptic pregnancies with genes associated with growth failure, blood pressure (BP), and chronic heart failure augmented in male HUVECs, whereas genetic variants for heart disease, pulmonary hypertension, congenital heart disease, and cardiac dysfunction were enhanced in female HUVECs. Overall, HUVECs from females were more impacted (almost 5-fold greater) than HUVECs from men in preeclamptic pregnancies, and 72% of preeclampsia-dysregulated genes in female HUVECs were downregulated, whereas 90% were upregulated in men. Pathways for eNOS (endothelial NO synthase) signaling were enriched in male and female HUVECs alike; however, enrichment of NF-κB (nuclear factor-κB), TGF (transforming growth factor)-β1, and proinflammatory cytokines was specific to females. Using gene arrays, a study by Lorenz et al reported greater enrichment of immune-related genes in female HUVECs. Although this study by Lorenz et al did not determine the effect of preeclampsia on sex-specific transcriptional differences in HUVECs, it does complement the sex-specific transcriptional differences observed by Zhou et al in this issue of Hypertension. Both studies reported that sex-specific changes in gene expression corresponded to sex differences in endothelial function. Yet, the relevance of HUVEC functionality to long-term pathophysiological outcomes in the offspring and whether sex differences in the expression of genetic factors and endothelial cell functionality in HUVECs can be interpreted to predict sex differences in long-term chronic health in the offspring is not clear. Numerous studies indicate that BP is elevated in individuals born to women with preeclampsia; yet, studies investigating sex differences in BP and cardiovascular risk in the offspring are very limited. Palti and Rothschild reported that systolic BP was higher at age 6 in boys and girls from mothers with preeclampsia relative to controls but the increase in systolic BP in girls was not significant. Seidman et al reported that systolic BP was higher at age 17 in girls but not boys whose mothers had preeclampsia. Experimental models that mimic the many facets of preeclampsia also indicate that the development of increased cardiovascular risk occurs at a younger age in male versus female offspring. The model of reduced uterine perfusion pressure in the pregnant rat mimics the many facets of preeclampsia and results in increased BP in male offspring as early as 4 weeks of age. However, BP is not increased in female offspring until 12 months of life. Prenatal hypoxia—a consequence of preeclampsia—is associated with impaired cardiovascular function in male offspring in early adulthood, whereas female offspring are not compromised until one year after birth. The rodent model of preeclampsia induced by chronic elevations in soluble vascular endothelial growth factor receptor-1 also programs a sex-specific increase in BP in the offspring with BP increased in male but not female offspring in early life. Collectively, these studies suggest that cardiovascular risk develops at a younger age in male offspring relative to females. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Departments of Cell and Molecular Biology (J.F.R.), Pharmacology and Toxicology (B.L.), and Physiology and Biophysics (B.T.A.), University of Mississippi Medical Center Jackson, MS; Mississippi Center of Excellence in Perinatal Research (J.F.R., B.L., V.G., B.T.A.); and Departments of Internal Medicine (V.G.) and Hypertension and Nephrology (V.G.), Mayo Clinic, Rochester, MN. Correspondence to Jane F. Reckelhoff, Department of Cell and Molecular Biology, Women’s Health Research Center, University of Mississippi Medical Center, Jackson, MS 39216. Email [email protected] Human Umbilical Venous Endothelial Cells: Early Predictors of Cardiovascular Risk in Offspring? What Is Known and What More Needs to Be Investigated?