Programmed cycle-induced endometrial perturbations do not independently influence angiogenic imbalance or hypertensive disorders in pregnancy
David Huang, Emily Flynn, Brittany Davidson, Juan C. Irwin, Mohammad Naser, Ana Laura Almonte, Jennifer Qin, Yue Song, Fleurdeliza B. Rabara, Rebecca Wong, Lydia B. Zablotska, Mitchell P. Rosen, Torsten Wittmann, Gabriela K. Fragiadakis, Alexis J. Combes, Marina Sirota, Marcelle I. Cedars, Linda C. Giudice
David Huang, Emily Flynn, Brittany Davidson, Juan C. Irwin, Mohammad Naser, Ana Laura Almonte, Jennifer Qin, Yue Song, Fleurdeliza B. Rabara, Rebecca Wong, Lydia B. Zablotska, Mitchell P. Rosen, Torsten Wittmann, Gabriela K. Fragiadakis, Alexis J. Combes, Marina Sirota, Marcelle I. Cedars, Linda C. Giudice
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Clinical Research and Public Health Clinical Research Reproductive biology

Programmed cycle-induced endometrial perturbations do not independently influence angiogenic imbalance or hypertensive disorders in pregnancy

Abstract

BACKGROUND In vitro fertilization (IVF) culminates in embryo transfer into a hormonally primed endometrium, often via a programmed cycle (PC) regimen postulated to influence hypertensive disorders of pregnancy (HDP) risk. We thus generated a single-cell atlas of PC endometrium to define cell type–specific differences relative to natural cycle (NC) endometrium and evaluated whether PC-associated modulation of the window of implantation (WOI) endometrium influences angiogenic balance in pregnancy.METHODS snRNA-seq of prospectively collected PC and NC WOI endometrium. An independent prospective cohort of 548 singleton pregnancies was separately analyzed for maternal serum angiogenic markers (soluble fms-like tyrosine kinase-1; placental growth factor) and HDP incidence in PC- versus NC-conceived pregnancies, adjusting for clinical confounders and IVF use.RESULTS Prominent transcriptomic differences were observed between PC (n = 7; 48,843 nuclei) and NC (n = 9; 44,230 nuclei) WOI endometrium, particularly in glandular epithelium (682 up- and 979 downregulated genes; Padj < 0.05) and stromal fibroblasts (108 up- and 168 downregulated). PC endometrium showed reduced uterine natural killer cell abundance, potentially from CXCL14 downregulation. Functional enrichment revealed downregulation of embryo implantation, angiogenesis, and extracellular matrix remodeling pathways in PC. Altered cell-cell signaling in decidualization, angiogenesis and inflammatory response were also observed. Despite these WOI perturbations, PC-conceived pregnancies were not associated with early gestational angiogenic imbalance or increased HDP risk.CONCLUSION PC endometrial preparation induced distinct cellular and signaling alterations in the WOI but was not associated with subsequent development of angiogenic imbalance or HDP, thereby underscoring the resilience and adaptability of the early maternal-fetal interface.TRIAL REGISTRATION ClinicalTrials.gov NCT03799107.FUNDING ABOG/AAOGF; NICHD-R01-HD084380; NCTRI-P50-HD055764; NIAMS-P30-AR070155.

Authors

David Huang, Emily Flynn, Brittany Davidson, Juan C. Irwin, Mohammad Naser, Ana Laura Almonte, Jennifer Qin, Yue Song, Fleurdeliza B. Rabara, Rebecca Wong, Lydia B. Zablotska, Mitchell P. Rosen, Torsten Wittmann, Gabriela K. Fragiadakis, Alexis J. Combes, Marina Sirota, Marcelle I. Cedars, Linda C. Giudice

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Figure 5

Angiogenic balance and incidences of hypertensive disorders of pregnancy by mode of conception.

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Angiogenic balance and incidences of hypertensive disorders of pregnancy...
(A) Study design of a prospective clinical cohort to investigate the effect of PC endometrium on angiogenic balance and risk of HDP, adjusting for underlying infertility and use of ART. (B) Serum levels of angiogenic markers (sFlt1 and PlGF; mean ± SEM) by mode of conception across various gestational periods. Kruskal-Wallis test used. (C) Ratios of sFlt-1:PlGF by mode of conception and gestational period. Kruskal-Wallis test used. (D) Incidences of HDP (composite), preeclampsia (PreE), preeclampsia with severe features (PreE with SF), and preterm preeclampsia with severe features (Preterm PreE with SF; disease diagnosis < 37 weeks GA) by mode of conception (P value by χ2 test).