# Redox Regulation in the Perinatal Pulmonary Vasculature

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2020 · $444,436

## Abstract

SUMMARY
Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth affecting 30% of infants with
birthweights < 1000 grams. Recently, pulmonary hypertension (PH) and right ventricular hypertrophy (RVH)
have been recognized as complications in approximately 25% of infants with moderate or severe BPD. Once
infants develop PH, little is known about how to treat them, and risk of morbidity and mortality is very high. One
of the mainstays of BPD therapy is oxygen (O2), but supraphysiologic O2 concentrations in combination with
mechanical ventilation increase reactive oxygen species (ROS) production, inducing significant vascular
dysfunction in neonates. Potential key targets for ROS-mediated dysregulation in the pulmonary vasculature
are involved in cGMP signaling - soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). In the
previous funding period, we utilized a mouse model of hyperoxia-induced lung disease and PH to demonstrate
that hyperoxia-exposed mice develop significant pulmonary and vascular disease, characterized by alveolar
simplification, fewer capillaries, small pulmonary arteries (PA) remodeling, and RVH. We demonstrated that
hyperoxia rapidly decreased lung and PA soluble guanylate cyclase (sGC) expression and activity and
increased lung and PA phosphodiesterase 5 (PDE5) activity, leading to disruption of cGMP-mediated
downstream signaling. Giving low-dose sildenafil, a PDE5 inhibitor, concurrent with hyperoxia prevented
increased PDE5 activity, vascular remodeling, and RVH, but was unable to restore normal capillary density
and alveolarization. In preliminary data for this proposal, we have demonstrated that another environmental
stressor, intrauterine growth restriction (IUGR) due to placental insufficiency, leads to a significant delay in
alveolarization with decreased expression of a key lung growth factor, insulin-like growth factor-1 (IGF-1),
decreased sGC expression and activity, and impaired alveolarization. IUGR mice have an exaggerated
phenotype with hyperoxia vs. appropriately grown mice with further decreased sGC expression and activity
and impaired alveolarization. We hypothesize that both growth restriction and hyperoxia-induced
mitochondrial ROS disrupt the critical sGC-cGMP signaling pathway, leading to impaired
alveolarization and angiogenesis. We will utilize our established mouse model of hyperoxia-induced lung
injury in combination with a novel model of IUGR to elucidate the molecular mechanism by which ROS and
growth restriction disrupt sGC-cGMP signaling and lung development. These studies will provide the
pathophysiologic, mechanistic framework to improve pharmacologic treatment of BPD infants with PH. We
believe sGC is a key integrator for multiple signals that impact alveolarization and angiogenesis in the neonatal
period. sGC stimulators such as riocinguat are approved in adults with PH and represent a novel and
potentially immediate therapeutic option for BPD-PH infants if a rationale...

## Key facts

- **NIH application ID:** 10018670
- **Project number:** 5R01HL109478-10
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** PAUL T SCHUMACKER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $444,436
- **Award type:** 5
- **Project period:** 2019-08-04 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018670

## Citation

> US National Institutes of Health, RePORTER application 10018670, Redox Regulation in the Perinatal Pulmonary Vasculature (5R01HL109478-10). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10018670. Licensed CC0.

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