# VEGF signaling in placental development and disease

> **NIH NIH R01** · UNIVERSITY OF MISSOURI KANSAS CITY · 2021 · $328,661

## Abstract

Every year over 300,000 women die from pregnancy complications, and over 6.5 million more suffer
complications that result in life-long disability, for which $41 billion is spent on healthcare costs. However, little
is known about the development and differentiation of the cells—extravillous trophoblasts (EVTs)—at the heart
of most human pregnancy complications. Our overarching goal is to develop mechanism-based strategies to
prevent, diagnose, and treat pregnancy complications associated with faulty trophoblast development. We
have strong evidence that vascular endothelial growth factor (VEGF) acts directly on trophoblast stem cells
and plays a key role in the differentiation of junctional zone cells and specific subtypes of trophoblast giant
cells (TGCs) in mice, which are orthologous to EVTs in humans. We discovered that different levels of decidual
VEGF overexpression at the implantation site stimulates placental production of the potent endogenous VEGF
antagonist soluble fms-like tyrosine kinase 1 (sFlt1) and induces a spectrum of symptoms in mice similar to
those of human obstetrical diseases, from preeclampsia to abruptio placentae. Our preliminary data show that
specific symptoms of each of those diseases are associated with abnormal development of a subset of TGCs
and junctional zone cells. Thus, we hypothesize that the level of VEGF overexpression during early placental
development corresponds to abnormal development of specific subtypes of TGCs associated with distinct
pregnancy complications and that the diseases associated with excess sFlt1 production can be treated by
reducing sFlt1 only at later stages of pregnancy. We also hypothesize that different EVT subtypes exist and
that excess VEGF can cause disproportionate expansion of specific EVT subtypes in humans. Thus, our
experiments will define the role of VEGF in the development of specific trophoblast subtypes (Aim 1), how
levels of VEGF affect these cells at each stage of placental development in vivo in the mouse, how these
cellular defects are related to specific pregnancy outcomes (Aim 2), and where and when VEGF signaling
pathways can be targeted for prevention and therapeutic strategies (Aim 2). Several novel techniques will be
used to address these questions, including inducible placenta- and decidua-specific gene expression systems
for precise control of gene expression at discrete stages of pregnancy, and nanoparticle-mediated delivery of
morpholinos to specific cells in the placenta. Finally, our preliminary data suggest that analogous EVTs may be
present at similar locations in the human placenta as TGCs in mice and that VEGF may play a similar role in
human trophoblast differentiation. We will characterize the diversity of EVTs in human placenta using laser
microdissection, global transcriptional profiling, and a culture model of human chorionic trophoblast progenitor
cell differentiation (Aim 3). These studies will characterize the previously unappreciated relationsh...

## Key facts

- **NIH application ID:** 10159946
- **Project number:** 5R01HD088549-06
- **Recipient organization:** UNIVERSITY OF MISSOURI KANSAS CITY
- **Principal Investigator:** Nihar R Nayak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $328,661
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159946

## Citation

> US National Institutes of Health, RePORTER application 10159946, VEGF signaling in placental development and disease (5R01HD088549-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10159946. Licensed CC0.

---

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