# Role of Endothelial Anoctamin-1 in Pulmonary Arterial Hypertension

> **NIH NIH R01** · OCEAN STATE RESEARCH INSTITUTE, INC. · 2022 · $391,771

## Abstract

ABSTRACT
Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. PAH pathology
includes vasoconstriction, medial and adventitial remodeling, and microvascular endothelial cell (EC)
proliferation leading to vaso-occlusive plexiform lesions. EC in PAH are both apoptosis resistant and
hyperproliferative. There are no effective treatments for the severe vascular remodeling observed with PAH,
and therapeutic strategies that target the dysfunctional EC and plexiform lesions are urgently needed. We
have discovered that calcium activated chloride channel, Ano1, is localized to both the EC plasma membrane
(pl-Ano1) and mitochondria (mito-Ano1). Ano1 expression is upregulated in EC in settings of PAH and
associated with a hyperproliferative and apoptosis resistant phenotype. However, unregulated activation of this
channel results in apoptosis of hyperproliferative apoptosis-resistant ECs. Our overall objective in this
proposal is to delineate the mechanisms underlying these seemingly conflicting observations to identify
therapeutic opportunities to decrease EC proliferation and target hyperproliferative ECs for apoptosis, thereby
improving pulmonary vascular remodeling in PAH. We hypothesize that epigenetically regulated increased
expression of Ano1 results in EC proliferation and apoptosis resistance, yet unregulated opening of Ano1 in the
context of overexpression is detrimental and can potentially be exploited to promote apoptosis of
hyperproliferative ECs in PAH. In Aim 1, we will determine the mechanism of increased Ano1 expression in
PAH EC with a focus on DNA methylation. We will use complementary in vitro and in vivo approaches to
design novel constructs to selectively alter the methylation pattern of Ano1 regulatory elements in lung EC and
test if this strategy prevents or treats PAH. In Aim 2, we will determine the effect of increased pl- and mito-
Ano1 expression on EC proliferation and apoptosis resistance and elucidate the underlying mechanisms. We
will investigate the signaling pathways in vitro and then use selective inhibition of Ano1 expression in lung EC
in vivo to determine its effect on preventing or treating PAH. In Aim 3, we will determine the mechanism of the
effect of pl- and mito-Ano-1 opening on EC apoptosis in vitro and test if opening of Ano1 by a small molecule
delivered by inhalation attenuates PAH. As a result of these studies we expect to delineate the mechanism of
Ano1-mediated EC proliferation and apoptosis resistance in settings of PAH as well as develop novel
therapeutic strategy targeting Ano1 to improve pulmonary vascular remodeling and PAH.

## Key facts

- **NIH application ID:** 10449284
- **Project number:** 5R01HL148727-04
- **Recipient organization:** OCEAN STATE RESEARCH INSTITUTE, INC.
- **Principal Investigator:** Gaurav Choudhary
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $391,771
- **Award type:** 5
- **Project period:** 2019-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449284

## Citation

> US National Institutes of Health, RePORTER application 10449284, Role of Endothelial Anoctamin-1 in Pulmonary Arterial Hypertension (5R01HL148727-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10449284. Licensed CC0.

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