# Role of VEGF in Perinatal Hypertension

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $670,560

## Abstract

Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows premature birth, remains a major cause of
morbidity and mortality. BPD is characterized by an arrest of vascular and alveolar growth and high risk for pulmonary
hypertension (PH), yet mechanisms contributing to its pathogenesis and early strategies to prevent BPD are poorly
understood. Strong epidemiologic studies have shown that the “new BPD” largely reflects the long-lasting impact of
antenatal factors on lung development partly due to vascular dysfunction, yet data from animal models that reflect the
prenatal timing of lung injury to parallel these observations are limited. Our recent prospective clinical studies have shown
that antenatal determinants as assessed on the first day of life and early echocardiogram findings of PH are strongly
linked with the subsequent diagnosis of BPD at 36 weeks PMA. As highlighted in recent NIH workshops, studies that define
mechanisms through which antenatal stress increases the risk for BPD and PH and early strategies that accurately identify
at-risk preterm infants are high research priorities. We have previously shown that disruption of vascular endothelial growth
factor (VEGF) signaling impairs lung vascular growth, decreases alveolarization and causes PH in experimental BPD, and
that the effects of VEGF are largely mediated through increased endothelial production of “angiocrine factors,” which
mediate endothelial-epithelial interactions and are necessary for normal distal lung growth. Based on work from our prior
funding period, we hypothesize that antenatal stress disrupts angiogenic signaling and impairs the production of critical
angiocrine factors in the fetal lung that lead to sustained abnormalities of lung structure and PH after birth. More
specifically, based on published and strong preliminary data, we seek to determine whether antenatal disruption of hypoxia-
inducible factor (HIF) and insulin-like growth factor 1 (IGF-1) signaling contributes to the pathogenesis of BPD and whether
enhancement of HIF and IGF-1 signaling are therapeutic strategies that would augment lung VEGF activity and have other
beneficial effects for BPD prevention. We propose a series of translational studies that link in vivo models of preeclampsia
and chorioamnionitis with in vitro studies using lung explants, isolated cell systems and molecular approaches to determine
whether augmentation of VEGF activity and related downstream pathways through modulation of HIF or IGF-1 signaling
can be targeted for developing new preventive therapies. To translate these findings to human disease, we propose to identify
early changes in proteomic markers of angiogenic pathways to link antenatal stress with high risk for BPD from our clinical
database. Finally, we will further apply novel imaging strategies to precisely define the impact of antenatal stress on distal
lung architecture, cell-specific changes in gene expression in vivo, and endothelial-epithelial cel...

## Key facts

- **NIH application ID:** 9975200
- **Project number:** 5R01HL068702-14
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Steven Herbert Abman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $670,560
- **Award type:** 5
- **Project period:** 2001-06-20 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975200

## Citation

> US National Institutes of Health, RePORTER application 9975200, Role of VEGF in Perinatal Hypertension (5R01HL068702-14). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9975200. Licensed CC0.

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