TY - JOUR
T1 - Sexual Dimorphisms of Preeclampsia-Dysregulated Transcriptomic Profiles and Cell Function in Fetal Endothelial Cells
AU - Zhou, Chi
AU - Yan, Qin
AU - Zou, Qing Yun
AU - Zhong, Xin Qi
AU - Tyler, Chanel T.
AU - Magness, Ronald R.
AU - Bird, Ian M.
AU - Zheng, Jing
N1 - Funding Information:
This study is supported by the American Heart Association award 17POST33670283 (C. Zhou) and National Institutes of Health grants P01HD38843 (J. Zheng, R.R. Magness, and I.M. Bird), P01HD038843-14S1 (J. Zheng and I.M. Bird), R01HL117341 (J. Zheng and R.R. Magness).
Funding Information:
We thank the University of Wisconsin Biotechnology Center DNA Sequencing Facility and Bioinformatics Resource Center for providing RNAseq and bioinformatics facilities and services. We thank Lori Uttech-Hanson, a grant writer from the Office of Research Administration and Proposal Development, UW-Madison for English editing.
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - Preeclampsia impairs fetoplacental vascular function and increases risks of adult-onset cardiovascular disorders in children born to preeclamptic mothers, implicating that preeclampsia programs fetal vasculature in utero. However, the underlying mechanisms remain elusive. We hypothesize that preeclampsia alters fetal endothelial gene expression and disturbs cytokines- and growth factors-induced endothelial responses. RNA sequencing analysis was performed on unpassaged human umbilical vein endothelial cells (HUVECs) from normotensive and preeclamptic pregnancies. Functional assays for endothelial monolayer integrity, proliferation, and migration were conducted on passage 1 HUVECs from normotensive and preeclamptic pregnancies. Compared with normotensive cells, 926 and 172 genes were dysregulated in unpassaged female and male HUVECs from preeclamptic pregnancies, respectively. Many of these preeclampsia-dysregulated genes are associated with cardiovascular diseases (eg, heart failure) and endothelial function (eg, cell migration, calcium signaling, and endothelial nitric oxide synthase signaling). TNF (tumor necrosis factor)-α-, TGF (transforming growth factor)-β1-, FGF (fibroblast growth factor)-2-, and VEGFA (vascular endothelial growth factor A)-regulated gene networks were differentially disrupted in unpassaged female and male HUVECs from preeclamptic pregnancies. Moreover, preeclampsia decreased endothelial monolayer integrity in responses to TNF-α in both female and male HUVECs. Preeclampsia decreased TGF-β1-strengthened monolayer integrity in female HUVECs, whereas it enhanced FGF-2-strengthened monolayer integrity in male HUVECs. Preeclampsia promoted TNF-α-, TGF-β1-, and VEGFA-induced cell proliferation in female, but not in male HUVECs. Preeclampsia inhibited TNF-α-induced cell migration in female HUVECs, but had an opposite effect on male HUVECs. In conclusion, preeclampsia differentially dysregulates cardiovascular diseases- and endothelial function-associated genes/pathways in female and male fetal endothelial cells in association with the sexual dimorphisms of preeclampsia-dysregulated fetal endothelial function.
AB - Preeclampsia impairs fetoplacental vascular function and increases risks of adult-onset cardiovascular disorders in children born to preeclamptic mothers, implicating that preeclampsia programs fetal vasculature in utero. However, the underlying mechanisms remain elusive. We hypothesize that preeclampsia alters fetal endothelial gene expression and disturbs cytokines- and growth factors-induced endothelial responses. RNA sequencing analysis was performed on unpassaged human umbilical vein endothelial cells (HUVECs) from normotensive and preeclamptic pregnancies. Functional assays for endothelial monolayer integrity, proliferation, and migration were conducted on passage 1 HUVECs from normotensive and preeclamptic pregnancies. Compared with normotensive cells, 926 and 172 genes were dysregulated in unpassaged female and male HUVECs from preeclamptic pregnancies, respectively. Many of these preeclampsia-dysregulated genes are associated with cardiovascular diseases (eg, heart failure) and endothelial function (eg, cell migration, calcium signaling, and endothelial nitric oxide synthase signaling). TNF (tumor necrosis factor)-α-, TGF (transforming growth factor)-β1-, FGF (fibroblast growth factor)-2-, and VEGFA (vascular endothelial growth factor A)-regulated gene networks were differentially disrupted in unpassaged female and male HUVECs from preeclamptic pregnancies. Moreover, preeclampsia decreased endothelial monolayer integrity in responses to TNF-α in both female and male HUVECs. Preeclampsia decreased TGF-β1-strengthened monolayer integrity in female HUVECs, whereas it enhanced FGF-2-strengthened monolayer integrity in male HUVECs. Preeclampsia promoted TNF-α-, TGF-β1-, and VEGFA-induced cell proliferation in female, but not in male HUVECs. Preeclampsia inhibited TNF-α-induced cell migration in female HUVECs, but had an opposite effect on male HUVECs. In conclusion, preeclampsia differentially dysregulates cardiovascular diseases- and endothelial function-associated genes/pathways in female and male fetal endothelial cells in association with the sexual dimorphisms of preeclampsia-dysregulated fetal endothelial function.
KW - endothelial dysfunction
KW - hypertension
KW - sex characteristics
KW - transcriptome
KW - umbilical veins
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UR - http://www.scopus.com/inward/citedby.url?scp=85068198274&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.118.12569
DO - 10.1161/HYPERTENSIONAHA.118.12569
M3 - Article
C2 - 31154903
AN - SCOPUS:85068198274
SN - 0194-911X
VL - 74
SP - 154
EP - 163
JO - Hypertension
JF - Hypertension
IS - 1
ER -