# New driver of fibrosis and calcification in CAVD

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $587,189

## Abstract

Project Summary
This research project will test the hypothesis that sortilin is a key regulator of fibrocalcific responses in
calcific aortic valve disease (CAVD) through promotion of myofibroblast-like collagen producing valvular
interstitial cells (VIC) phenotype and induction of VIC-derived extracellular vesicle (EVs) calcification. The
role of sortilin in CAVD has never been investigated. Our unbiased network-based systems biology
approach found that sortilin network is highly significantly close to the p38 MAPK protein network. In
addition, single cell RNA sequencing of sortilin-expressing VICs identified enrichment of major biological
pathways, including cytoskeletal organization, vesicle transport and calcification, thus suggesting that
sortilin participates in CAVD by inducing myofibroblast-like phenotype, fibrosis and calcification in VICs,
previously unknown functions of sortilin. The present study will explore the role of sortilin in aortic valve
calcification and focus on these key pathways in our mechanistic studies. Specific Aim 1 will test the
hypothesis in vivo that sortilin accelerates fibrocalcific responses in the aortic valve. These experiments will
be performed in a mouse model of calcific aortic stenosis using sortilin-deficient mice, a compound mutant
strain recently established in PIs laboratory, and human aortic valve leaflets containing minimal calcification
obtained from patients with CAVD. Under control of molecular imaging, the portions of these leaflets
representing early CAVD (e.g., fibrosis, microcalcification) will be dissected and used for our analyses. In
addition, we will employ innovative methods for detection of EV-derived microcalcifications and VIC
phenotypes, including density dependent scanning electron microscopy (DD-SEM), high-resolution
microscopy, nanoparticle tracking analysis, 3D-bioprinted hydrogel platform, proteomics, single cell
analyses, and complex network analyses. Specific Aim 2 will test the hypothesis in vitro that sortilin
mediates VIC fibrocalcific response by promoting VIC myofibroblast-like phenotype, collagen production,
and the release and mineralization of EVs; further aggregation of EVs within newly formed collagen fibers
results in the formation of microcalcifications. We propose that sortilin induces VIC fibrocalcific responses
and that genetic deletion of sortilin will decrease collagen production and retard the formation of
microcalcifications in human VICs and mice. To facilitate clinical translation of mouse data, we will employ
human primary VICs and aortic valve specimens from patients with CAVD. These complementary studies
will advance the field by examining the role of sortilin in early CAVD. In the long-term, the findings from this
project will identify novel molecular determinants that drive CAVD, and define new targets for much-needed
therapies for patients with this devastating disorder.

## Key facts

- **NIH application ID:** 10150536
- **Project number:** 5R01HL147095-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Elena Aikawa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $587,189
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150536

## Citation

> US National Institutes of Health, RePORTER application 10150536, New driver of fibrosis and calcification in CAVD (5R01HL147095-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10150536. Licensed CC0.

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