# Aquaporin 1 and pulmonary hypertension

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $718,982

## Abstract

PROJECT SUMMARY
 Pulmonary arterial hypertension (PAH) is a severely debilitating disease with no cure. Morphometric
studies revealed that the development of pulmonary hypertension is associated with robust structural
remodeling of the small pulmonary arteries, characterized by thickening of the endothelial and smooth muscle
cell layers and formation of occlusive lesions. In addition to increased proliferation and migration of vascular
cells, failure of appropriate apoptosis (i.e., apoptotic resistance) contributes to remodeling via lack of cell
turnover. Our laboratory identified a new candidate as a regulator of pulmonary arterial smooth muscle cell
(PASMC) function: aquaporins (AQPs). AQPs are a family of proteins that form transmembrane channels
which facilitate the transport of water into and out of cells. We have evidence that aquaporin 1 (AQP1), the first
family member identified, is expressed in PASMCs and pulmonary microvascular endothelial cells (PMVECs),
upregulated in a rat model of PAH and modulates susceptibility to apoptosis. Our preliminary data also indicate
that increased AQP1 protein is associated with elevated β-catenin expression, a protein that regulates
migratory, proliferative and survival responses. The mechanism by which AQP1 regulates β-catenin levels is
currently unknown; we have generated exciting data indicating a critical role for a specific region of the AQP1
C-terminal tail. This region contains a previously unrecognized putative binding site for GSK3β, an endogenous
regulator of β-catenin abundance. Based on these data, we hypothesize that in PAH PASMCs and PMVECs,
increased AQP1 levels contribute to cell growth and survival by sequestering GSK3β and reducing its
activity/nuclear localization; as a consequence, β-catenin accumulates, promoting migration and proliferation
and preventing apoptosis. The Aims of this study are to: 1) determine whether AQP1 regulates β-catenin via
binding to GSK3β; 2) identify the mechanism by which AQP1 facilitates cell growth and survival; and 3)
evaluate whether cell-specific disruption of AQP1 prevents or reverses PAH.

## Key facts

- **NIH application ID:** 10895497
- **Project number:** 5R01HL126514-07
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Larissa A. Shimoda
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $718,982
- **Award type:** 5
- **Project period:** 2014-12-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895497

## Citation

> US National Institutes of Health, RePORTER application 10895497, Aquaporin 1 and pulmonary hypertension (5R01HL126514-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10895497. Licensed CC0.

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