# Role of Hypoxia in Regulating Stromal-Epithelial Communication during Pregnancy

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2022 · $307,774

## Abstract

Implantation is initiated when the blastocyst attaches to the uterine luminal epithelium and subsequently
penetrates into the underlying stroma to firmly embed into the endometrium. While many aspects of
implantation remain unclear, emerging evidence indicates that intercellular communication between
endometrial epithelial and stromal cells is vital for successful establishment of pregnancy. The paracrine
signals that mediate this crosstalk remain poorly understood. Our recent studies revealed that the
transcription factor, hypoxia-­‐inducible factor 2 alpha (HIF2α), is induced selectively in endometrial stromal
cells subjacent to the luminal epithelium at the time of implantation. This finding is significant because it is
known for a long time that the maternal environment during implantation is hypoxic. To address the
mechanisms of maternal adaptation to hypoxia during implantation, we generated Hif2αd/d mice that
conditionally lack HIF2α in the endometrium. In these mice, the blastocysts are closely apposed to the uterine
epithelium but fail to sustain firm attachment to it, resulting in implantation failure. The uterine stromal cells of
Hif2αd/d mice exhibited downregulation of metabolic factors, such as lactate and a subset of amino acids, and
a distinct set of Rab GTPases that regulate secretion of extracellular vesicles (EVs), including microvesicles
and exosomes. The EVs are known to mediate a novel mechanism of cell-cell communication. That hypoxia
promotes EV secretion by certain cells support the concept that HIF2α-driven EV secretion by the endometrial
stromal cells represents a critical adaptive response that promotes intercellular communication during
implantation. In the proposed study, we will employ the Hif2αd/d mouse model to test the hypothesis that
HIF2α regulates a novel paracrine signaling mechanism under the hypoxic conditions of early pregnancy by
controlling EV trafficking in the maternal tissue and that it directs transfer of key signaling molecules and
metabolites from the stromal to luminal epithelial cells to influence epithelial functionality during implantation.
We have proposed three specific aims to test this hypothesis. In Aim 1, we will investigate HIF2α-mediated
EV trafficking in endometrial stromal cells and identify the resident molecular cargo in EVs. In Aim 2, we will
investigate the effects of EVs and metabolic factors secreted from endometrial stromal cells on the
functionality of epithelial cells. In Aim 3, we will investigate the role of HIF2α in regulating the secretory
function of human endometrial stromal cells. A multi-pronged approach, utilizing a combination of (i) a unique
animal model harboring a specific defect in adaptive response (ii) functional analyses using mouse and
human primary endometrial cells, and (iii) genomic and proteomic analyses to understand cell-to-cell
trafficking mechanisms, will enable us to provide answers to important unresolved questions regarding the
impact of hypoxia o...

## Key facts

- **NIH application ID:** 10406940
- **Project number:** 5R01HD090066-05
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** MILAN K BAGCHI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $307,774
- **Award type:** 5
- **Project period:** 2018-09-13 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406940

## Citation

> US National Institutes of Health, RePORTER application 10406940, Role of Hypoxia in Regulating Stromal-Epithelial Communication during Pregnancy (5R01HD090066-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10406940. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*