# Endothelial Reprogramming in Pulmonary Hypertension

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $389,555

## Abstract

Background: Pulmonary hypertension is a devastating vascular disease for which no current
cure exists. Despite a number of FDA-approved therapies, survival remains low and no current
therapy reverses the vascular remodeling in the pulmonary vasculature responsible for disease
progression. The pulmonary vascular endothelium is thought to play an important role in
initiating and promoting the PH-associated vascular remodeling. However, how this occurs
remains elusive and the phenotypic signature of the lung endothelium as the disease
progresses remains a challenging process to understand. We have recently shown that
changes in reactive oxygen species (ROS) driven by NADPH oxidase 1 (Nox1) are involved in
promoting pulmonary endothelial proliferative mechanisms in PH. We recently also linked Nox1
activity to the scaffolding protein ERM-binding phosphoprotein 50 (EBP50, aka NHERF1) in
systemic vascular cells, suggesting a role for EBP50 in the pulmonary vasculature. Preliminary
data demonstrate that in vitro modulation of human pulmonary arterial endothelial cells with PH-
related stimuli affects EBP50 expression and that in vitro and in vivo interruption in EBP50 leads
to exacerbated PH-related responses. Analysis utilizing PCR pathway arrays revealed
upregulation of endothelial-to-mesenchymal transition (EndMT) transcription factors potentially
in an EBP50 dependent manner in a PH mouse model. This proposal will test the causality of
this link and will assess the contribution of EndMT to vascular remodeling in PH and test
whether it occurs in an EBP50-dependent mechanism. Hypothesis: PH-induced perturbation of
EBP50 homeostasis promotes phenotypic reprogramming of pulmonary endothelial cells
leading to increased EndMT and vascular remodeling. Specific Aims: 1-) To test whether
attenuation of EBP50 is causally linked to development or worsening of PH; 2-) To test whether
EBP50 is an upstream negative modulator of EndMT in the pulmonary vascular endothelium;
and 3) To test whether therapeutic rescue of EBP50 homeostasis in attenuates EndMT and in
vivo manifestations of PH in preclinical models. Gain- and loss- of function techniques will be
used to sequentially and combinatorially target EBP50 and EndMT-related transcription factor in
vitro in pulmonary vascular cells subjected to PH-related stimuli. Knockout animals and
administration of recombinant proteins and/or blocking antibodies will be used in in vivo models
of PH. Finally, lineage tracing experiments will be used to assess EndMT in PH models.
Significance: Current PH drugs neither prevent nor reverse disease progression. If successful,
the proposal will uncover novel molecular mechanisms and reprogramming pathways in the
pulmonary vasculature that can be targeted for future PH drug development.

## Key facts

- **NIH application ID:** 9937810
- **Project number:** 5R01HL148712-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Imad Al Ghouleh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $389,555
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937810

## Citation

> US National Institutes of Health, RePORTER application 9937810, Endothelial Reprogramming in Pulmonary Hypertension (5R01HL148712-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9937810. Licensed CC0.

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