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

David Huang; Emily Flynn; Brittany R. 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

doi:10.1172/jci.insight.202443

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

David Huang,¹ Emily Flynn,² Brittany R. Davidson,² Juan C. Irwin,³ Mohammad Naser,² Ana Laura Almonte,⁴ Jennifer Qin,⁵ Yue Song,⁵ Fleurdeliza B. Rabara,¹ Rebecca Wong,¹ Lydia B. Zablotska,⁶ Mitchell P. Rosen,¹ Torsten Wittmann,² Gabriela K. Fragiadakis,² Alexis J. Combes,² Marina Sirota,⁴ Marcelle I. Cedars,¹ and Linda C. Giudice¹

Published June 23, 2026 - More info

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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. Single-nucleus RNA-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 down-regulated genes; adjusted P < 0.05) and stromal fibroblasts (108 up- and 168 down-regulated). 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 was 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.

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

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