# Interactions of SERCA2a and BMPRII in Vascular Disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $423,750

## Abstract

Pulmonary arterial hypertension (PAH) is characterized by an increase of pulmonary vascular resistance
leading to right ventricular overload and eventually to right ventricular failure and premature death. The
pathological mechanisms underlying this condition remains incompletely understood. While the exact causes
of PAH remain under investigation, it is widely recognized that the hallmarks of all forms of PH are sustained
vasoconstriction, endothelium dysfunction and vascular remodeling. Remodeling of pulmonary arteries is
characterized to varying degrees by thickening of the intimal and medial layer of muscular vessels resulting
from proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) with alterations in Ca2+
homeostasis. Diverse loss-of-function mutations in the conical BMPR2 gene, a component of the transforming
growth factor beta (TGFβ) family that plays a key role in cell growth and fibrosis, have been associated with
the majority of familial and sporadic cases of PAH. We have shown that sarco(endo)plasmic reticulum Ca2+-
ATPase 2a (SERCA2a) pump expression is decreased in small hypertrophied pulmonary arterioles from
patients with PAH and in a rat model of monocrotaline (MCT)-induced PAH. We also found that SERCA2a
expression is reduced in hypertrophied pulmonary arterial wall of patients with underlying BMPR2 mutations
and in transgenic SM22-tet-BMPR2delx4 mice, with a SMC-specific mutant form of BMPR2, known to develop
spontaneous PAH. Gene transfer of SERCA2a by an adenovirus resulted in decreased human PASMC
proliferation and migration via a mechanism involving STAT3/NFAT signaling pathways. In addition, SERCA2a
overexpression increased BMPR2, eNOS expression and activity and decreased STAT3/NFAT activity in
hPAEC. In addition, selective pulmonary SERCA2a gene transfer using aerosolized adeno-associated virus
serotype 1 (AAV1.SERCA2a) in MCT-PAH rat model attenuate pulmonary hypertension and RV hypertrophy,
and increased eNOS and BMPR2 expression. Based upon the preliminary findings we contend there is cross
talk between SERCA2a and BMPR2 with interdependent downstream signaling in pulmonary vascular that
affects pulmonary vascular structural remodeling and suggest that SERCA2a gene transfer may modulate
BMPR2 expression and/or dependent signaling pathways and therefore PAH phenotype. To test this
hypothesis we will: 1) Characterize the link between SERCA2a and BMPR2 in pulmonary vascular cells. 2)
Determine the effects of SERCA2-specific ablation in SMCs & ECs on PAH pathogenesis in a mouse model.
And 3) Investigate the therapeutic effects of SERCA2a overexpression using chemically modified messenger
RNA (modRNA) in transgenic animal models. The knowledge acquired through this proposal is significant
because by modulating SERCA2a expression, we will characterize its key role in BMPR2 expression and
signaling and therefore in pulmonary vascular remodeling and PAH phenotype, that may lead to the
identification...

## Key facts

- **NIH application ID:** 10000208
- **Project number:** 5R01HL133554-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Lahouaria HADRI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000208

## Citation

> US National Institutes of Health, RePORTER application 10000208, Interactions of SERCA2a and BMPRII in Vascular Disease (5R01HL133554-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10000208. Licensed CC0.

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