# Mechanotransduction and YAP/TAZ Signaling in Pulmonary Arterial Hypertension

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $633,187

## Abstract

PROJECT SUMMARY/ABSTRACT:
Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of apoptosis-resistant
pulmonary artery endothelial cells (PAEC), smooth muscle cells (PASMC), and adventitial fibroblasts (PAAF)
leading to progressive increases in pulmonary vascular resistance, and ultimately right heart failure and death.
Recent studies suggest that pulmonary arterial (PA) stiffness is associated with increased mortality in
patients with PAH; however, the mechanisms involved in the pathogenesis and progression of PA stiffening in
PAH have yet to be fully elucidated. We have discovered that distal vascular matrix stiffening develops early in
models of pulmonary hypertension (PH) and triggers a local mechanobiological feedback loop that amplifies
vascular remodeling and accelerates disease progression. These findings suggest that PA stiffness is not
merely a consequence of pathologic changes in the vessel wall, but can itself drive abnormal cellular behavior.
We have identified YAP and TAZ as pivotal regulators of stiffness-dependent PASMC and PAEC
mechanoactivation in PAH. Our preliminary findings suggest that mechanosignaling via YAP/TAZ drives
vascular cell activation through suppression of cyclooxygenase (COX)-2-derived prostanoid production and
bone morphogenetic protein (BMP) signaling. Silencing of YAP/TAZ in PASMC and PAEC abrogates stiffness-
dependent increases in proliferation, matrix deposition, and traction force generation, and rescues suppression
of prostanoid production and BMP signaling. Moreover, PASMC overexpressing a mutant TAZ that localizes
constitutively to the nucleus have a dramatic reduction in COX-2-derived prostanoid production and BMP
signaling leading to a hyperproliferative remodeling phenotype. We hypothesize that YAP/TAZ are activated by
the mechanical environment to drive pro-remodeling cellular responses and promote matrix stiffening in an
adverse feedback loop via suppression of prostanoid production and BMP signaling in PAH. In Aim 1, we will
investigate the role that YAP/TAZ play in regulating COX-2-dependent prostaglandin production and vascular
responses to matrix stiffening in PAH. We will determine the mechanisms of YAP/TAZ-dependent suppression
of COX-2 and regulation of stiffness-dependent contractility and matrix synthesis in human PASMC, PAEC,
and PAAF. In Aim 2, we will examine the mechanisms by which YAP/TAZ control TGF-! and BMP-dependent
Smad signaling, suppress Id1 expression, and regulate cellular growth responses to BMP signaling in PAH.
We will determine the impact of YAP/TAZ activity on proliferation, apoptosis resistance, and migration in
PASMC, PAEC, and PAAF from PAH patients with and without BMPR2 mutations. In Aim 3, we will determine
whether inactivation of YAP/TAZ arrests PA stiffening, attenuates vascular remodeling, and prevents right
ventricular (RV) dysfunction in experimental PH. We will use murine models and pharmacologic approaches to
modulate YAP/TAZ ac...

## Key facts

- **NIH application ID:** 9840934
- **Project number:** 5R01HL137366-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** LAURA ELIZABETH FREDENBURGH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $633,187
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840934

## Citation

> US National Institutes of Health, RePORTER application 9840934, Mechanotransduction and YAP/TAZ Signaling in Pulmonary Arterial Hypertension (5R01HL137366-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840934. Licensed CC0.

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