# Systems biology, endothelial regulation of fibrosis, and pulmonary vascular disease

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $432,096

## Abstract

Project Summary/Abstract
Early mortality in pulmonary arterial hypertension (PAH) is due, in part, to fibrotic remodeling of pulmonary arterioles
that increases vascular resistance, although effective therapies for vascular fibrosis in PAH do not exist currently.
Overlap among established signaling pathways that regulate collagen function in reparative (e.g., dermal wound
healing) and pathogenic (i.e., causing end-organ damage) fibrosis suggests that reductionist methods are limited for
identifying key mechanisms mediating vascular fibrosis in PAH. In this NIH Research Project Grant Program
proposal, we use network theory to develop a protein-protein interactome (fibrosome) and analyzed genes in silico
according to their association with dermal wound healing or vascular fibrosis. The pro-oxidant hormone aldosterone
(ALDO) promotes collagen synthesis in dermal wound healing. However, ALDO also increases collagen in human
pulmonary artery endothelial cells (HPAECs) in vitro to induce vascular fibrosis in PAH in vivo. Thus, we propose
that segregating ALDO-regulated genes in the fibrosome according to their association with pathogenic or adaptive
fibrosis will allow novel molecular targets responsible for arterial fibrillar collagen synthesis in PAH to emerge.
 From our network analysis, we predicted that regulation of the Cas-L protein NEDD9 by ALDO delineates
pathogenic from reparative fibrosis. We show that oxidation of a functionally essential cysteinyl thiol at position 18 of
NEDD9 by ALDO prevents binding of NEDD9 with Smad3, which is required for normal proteolytic degradation of
NEDD9. Impaired NEDD9-Smad3 binding, in turn, was associated with increased NEDD9 as well as NEDD9-
dependent fibrillar collagen III levels and collagen matrigel contraction in ALDO-treated HPAECs in vitro, but not in
cell types of reparative fibrosis. However, exosomes from ALDO-treated HPAECs increased NEDD9 in co-cultured
human pulmonary artery smooth muscle cells, which was consistent with our observation that NEDD9 was
increased globally in fibrotic pulmonary arterioles from PAH patients. Therefore, the central hypothesis of the
current proposal is that oxidative modification of NEDD9-Cys18 by ALDO is a key molecular mechanism
underpinning NEDD9 accumulation in HPAECs in vitro to promote pathogenic pulmonary vascular fibrosis
and PAH in vivo. We postulate further that NEDD9 upregulation and transcellular signaling involving endothelial
exosomes are two novel molecular mechanisms by which HPAECs promote vascular fibrosis in PAH. The study
Aims are: (1) use Raman spectroscopy to demonstrate definitively that NEDD9-Cys18 oxidation by ALDO is an
essential molecular mechanism underpinning a fibrotic phenotype in HPAECs in vitro, (2) test the hypothesis that
HPAECs contribute to vascular fibrosis via intercellular signaling through a mechanism involving exosomes, and (3)
use transgenic mice and gain-of-function methods to demonstrate that NEDD9 is a critical mediator ...

## Key facts

- **NIH application ID:** 10076637
- **Project number:** 5R01HL139613-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Bradley Maron
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,096
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076637

## Citation

> US National Institutes of Health, RePORTER application 10076637, Systems biology, endothelial regulation of fibrosis, and pulmonary vascular disease (5R01HL139613-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10076637. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*