# Endothelial mechanotransduction and metabolic remodeling

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2020 · $412,197

## Abstract

PROJECT SUMMARY
Pulmonary vascular disease (PVD) is an important source of morbidity and mortality in patients with congenital
heart disease (CHD). The natural history of PVD in these patients reveals the important pathophysiologic
differences associated with abnormal pulmonary blood flow (PBF) and pressure. Patients with cardiac defects
that expose the pulmonary vasculature to increased flow with a direct pressure stimulus from the systemic
ventricle develop PVD with greater incidence and severity than patients with defects resulting in increased PBF
alone. Pulmonary endothelial cells (EC) are integral mediators of disease, due to their exposure to these normal
and abnormal hemodynamic (mechanical) forces including shear stress, hydrostatic pressure, and cyclic strain.
Our laboratory has developed two distinct, clinically relevant models of CHD in fetal lambs: (1) left pulmonary
artery (LPA) ligation that primarily results in increased PBF to the right lung; and (2) aortopulmonary shunt
placement that results in increased PBF and pressure. Our preliminary data demonstrate that at 4-6 weeks of
age, model lambs manifest distinct aberrations in endothelial cell signaling and vascular function. For example,
RNAseq analysis performed on primary pulmonary artery endothelial cells (PAEC) from each lamb model
demonstrates markedly distinct gene expression patterns, and studies in isolated vessels demonstrate disparate
alterations in vascular reactivity. Moreover, we have generated novel in vivo and in vitro data demonstrating that
the additive effects of the biomechanical forces—fluid shear stress and pressure induced cyclic stretch—cause
perturbations in cellular signaling pathways that result in endothelial dysfunction (eNOS uncoupling), metabolic
reprogramming (ROS driven HIF-1a, and c-MYC activation), and a hyper-proliferative, anti-apoptotic, endothelial
cell phenotype. Based on these data, the overall hypothesis we will test in Project #1, is that the distinct
mechanical forces associated with increased PBF compared to increased PBF and pressure, induce patterned
alterations in gene expression and vascular function that underlie the incidence and progression of PVD
associated with CHD. Specifically, we hypothesize that flow-alone maintains NO signaling through ATP-
dependent hsp90 activity and c-MYC-mediated glutamine anaplerosis. The addition of pressure induced cyclic
stretch, however, leads to HIF-1α driven Warburg metabolism and EC hyper-proliferation via increases in
mitochondrial (mt)-ROS production, but at the expense of ATP-dependent hsp90 activity and NO signaling. This
overall hypothesis will be tested in three inter-related, but independent, Specific Aims. As current PVD treatment
approaches are based on disease severity as opposed to underlying pathobiology, the successful completion of
the proposed studies may lead to targeted therapeutic approaches for PVD 2° to CHD, as well as inform other
types of PVD, in which abnormal mechanical ...

## Key facts

- **NIH application ID:** 9937322
- **Project number:** 1P01HL146369-01A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** JEFFREY R FINEMAN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,197
- **Award type:** 1
- **Project period:** 2020-08-10 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937322

## Citation

> US National Institutes of Health, RePORTER application 9937322, Endothelial mechanotransduction and metabolic remodeling (1P01HL146369-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9937322. Licensed CC0.

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