# The Role of Placental Maternal Vascular Underperfusion in Neonatal Pulmonary Hypertension

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2020 · $523,142

## Abstract

PROJECT SUMMARY
Neonatal pulmonary hypertension (PH) is a serious condition that affects up to one third of premature infants
with bronchopulmonary dysplasia (BPD). This entity, known as BPD-associated PH (BPD-PH), is fully
established by 1-3 months of age and incurs a four-fold increased risk of death. Survivors of BPD-PH have
prolonged and recurrent hospitalizations, and are at risk for chronic cardiopulmonary and metabolic problems.
We are committed to developing targeted strategies to prevent BPD-PH in premature infants. Two promising
therapeutic targets are the histologic marker, placental maternal vascular underperfusion (MVU) and the
intermediate cord blood-derived fetal monocytes (iMNC) that circulate at birth. Our central hypothesis is that fetal
iMNCs are adversely programmed by the chronic fetal hypoxia of placental MVU, and contribute to early delayed
lung angiogenesis leading to BPD-PH. In Aim #1, we will elucidate the mechanism by which MVU leads to
delayed neonatal angiogenesis. Using fetal growth restriction (FGR, birth weight <5th percentile) as the proxy for
chronic fetal hypoxia, we will compare iMNC VEGFR1 expression via flow cytometric analysis of 100 cord blood
samples from the following groups of infants: 1) preterm MVU with FGR; 2) preterm MVU without FGR; 3) preterm
no MVU with FGR; 4) preterm no MVU no FGR (preterm control); 5) term no MVU no FGR (term control). In
isolated iMNCs, we will use PCR Array to compare the gene expression profiles of these groups and identify
novel gene targets and pathways driven by MVU. In Aim #2 we will identify the perinatal mechanisms by which
MVU-exposed fetal iMNCs contribute to delayed neonatal lung angiogenesis: In cultured iMNCs exposed to
experimental hypoxia and hyperoxia, we will evaluate VEGFA and VEGFR1 gene and protein expression. We
will perform chemotaxis assays to compare iMNC migration in response to exogenous treatment with placental
growth factor (PIGF) and granulocyte colony stimulating factor (GCSF), and we will compare iMNC expression
of VEGFR1 in bronchoalveolar lavage fluids from intubated preterm infants. Lastly, in Aim #3 we will transplant
iMNCs from the 5 patient groups into newborn human GM-CSF knock-in (humanized) mice, and follow the lung
histology and PH parameters after chronic hyperoxia exposure (85% oxygen x 14 days). We will test the
hypothesis that transplantation of cord blood-derived iMNCs from non-MVU, non-FGR infants (controls) will aid
in the prevention of BPD-PH.

## Key facts

- **NIH application ID:** 9868323
- **Project number:** 5R01HL139798-04
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Karen K Mestan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $523,142
- **Award type:** 5
- **Project period:** 2018-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868323

## Citation

> US National Institutes of Health, RePORTER application 9868323, The Role of Placental Maternal Vascular Underperfusion in Neonatal Pulmonary Hypertension (5R01HL139798-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9868323. Licensed CC0.

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