# Regulation of UPRmt activation in the development of pulmonary vascular remodeling in PAH

> **NIH NIH K01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $112,160

## Abstract

Project Summary/Abstract
Pulmonary Arterial Hypertension (PAH) is a severe and progressive disease with a high mortality rate of nearly
40% over 5 years. Pulmonary artery endothelial and smooth muscle cells (PAECs and PASMCs) undergo
intracellular signaling changes that promote a proliferative, apoptosis resistant phenotype that causes
occlusion of the pulmonary vasculature leading to increased resistance. There is a critical need to uncover the
mechanisms that promote vascular cell remodeling. Our long-term goal is to identify pathways or molecules to
target for therapeutic intervention in order to alleviate the vascular abnormalities that are central to PAH
development and progression. Sphk1 and sphingosine-1 phosphate are increased in the lungs and pulmonary
artery smooth muscle cells of PAH patients and in the lungs of rodent models of hypoxia mediated pulmonary
hypertension (HPH). Mitochondrial (mt) dysfunction also contributes to PAH via altered regulation of multiple
mt processes, which leads to impaired vasorelaxation and increased vascular cell proliferation. However, the
effect of the Sphk1/S1P signaling axis on mt function in the initiation or progression of PAH is not well
understood. Our preliminary studies demonstrate that S1P promotes activation of the UPRmt and regulates mt
dynamics in human PAECs and PASMCs. The specific objective of the proposed study is to determine the
role of UPRmt signaling mediators on vascular cell function. Our central hypothesis is that activation of the
Sphk1/S1P/S1PR signaling axis modulates the UPRmt pathway to promote vascular remodeling which leads to
PAH development. This hypothesis will be tested by investigating the following specific aims:
AIM 1: To investigate the role of the UPRmt in S1PRs/S1P/Sphk1 promotion of pulmonary vascular cell
proliferation and hypoxia induced PH (HPH) development. Our working hypothesis is that the Sphk1/S1P/
S1PR signaling axis modulates mitochondrial function, which is a central cause underlying the pathological
proliferation of PASMCs and PAECs to mediate PAH development.
AIM 2: To determine the effects of UPRmt inhibition on vascular remodeling and HPH development. Our
working hypothesis is that hypoxia induces activation of UPRmt in vivo resulting in vascular remodeling and
PAH.
AIM 3: Determine if coordinated signaling occurs between pulmonary vascular cells and mitochondrial
processes to regulate vascular remodeling and HPH. Our working hypothesis is that coordinated signaling
among the UPRmt, mitochondrial fission and mitochondrial respiration promote vascular remodeling.

## Key facts

- **NIH application ID:** 10508601
- **Project number:** 1K01HL164874-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Angelia Denise Lockett
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $112,160
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10508601

## Citation

> US National Institutes of Health, RePORTER application 10508601, Regulation of UPRmt activation in the development of pulmonary vascular remodeling in PAH (1K01HL164874-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10508601. Licensed CC0.

---

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