# Abnormal HIF signaling in Down syndrome-related pulmonary hypertension

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2022 · $233,250

## Abstract

PROJECT SUMMARY
Down syndrome (DS), the condition that arises from triplication of chromosome 21 (HSA21), occurs in 1:700 live
births and is the most common human chromosomal abnormality. A major co-occurring condition in DS is
pulmonary hypertension (PH), which can lead to progressive right heart dysfunction, failure, and death, even
when aggressively treated. Remarkedly, PH occurs very frequently in newborns and children with DS (28%)
when compared with non-DS subjects and can be associated with congenital heart disease. The underlying
cause of PH and the increased susceptibility to accelerated PH in in DS remain poorly understood and animal
models for preclinical studies of PH in DS have been lacking. Recent studies have shown that early disruption
of lung development related to impaired angiogenesis and alveolar growth is evident in DS children with severe
PH, but there remains a critical need to define specific genetic and molecular mechanisms that delay lung
maturation and increase susceptibility for PH. Furthermore, more selective PH therapies are needed to decrease
cardiopulmonary morbidity and mortality in DS. Past studies have suggested that individuals with DS have a low
incidence of vascular disease and solid tumors due to overexpression of anti-angiogenic factors, but whether
disruption of lung vascular growth is due to abnormal regulation of angiogenesis and related alveolar
growth and mechanisms that contribute to PH in DS children remain uncertain. Our laboratory has
previously demonstrated that inhibition of angiogenic pathways reduces lung alveolar and vessel growth and
causes PH in diverse experimental models. Additionally, we showed that HSA21-encoded potent anti-angiogenic
genes are overexpressed in human fetal and neonatal DS lung and show evidence for reduced vascular and
alveolar growth, even in the absence of cardiac disease. In line with these findings, our human biomarker studies
show that serum anti-angiogenic factor profile is strongly associated with PH in DS children. Our preliminary data
show that 2 weeks of very mild hypoxia exposure of Dp16 DS mice leads to PH as characterized by increased
pulmonary vascular wall thickening, decreased vascular densities and right ventricular hypertrophy, and delays
lung maturation. Such delayed lung maturation and PH development in DS animal model has not been previously
studied, and Dp16 DS mice appears to be a valid preclinical model of PH in DS. Hypoxia and hypoxia-inducible
(HIF) signals are critical in PH and abnormal lung development, and cells of DS are characterized by pseudo-
hypoxic state that drives a variety of functional deficits seen in DS. Our preliminary data show that hypoxia
inducible gene network is markedly upregulated with significant alteration in the molecular pathways that regulate
pulmonary vessel development and response to hypoxia in this model. Thus, we hypothesize that mild
hypoxic exposure of Dp16 neonatal mice leads to the development of PH and dela...

## Key facts

- **NIH application ID:** 10519030
- **Project number:** 1R21HL165364-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Csaba Galambos
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $233,250
- **Award type:** 1
- **Project period:** 2022-09-06 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10519030

## Citation

> US National Institutes of Health, RePORTER application 10519030, Abnormal HIF signaling in Down syndrome-related pulmonary hypertension (1R21HL165364-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10519030. Licensed CC0.

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