# Novel Regulators of Calcific Aortic Valve Disease

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $707,264

## Abstract

Aortic stenosis is the most common cause of valvular heart disease and calcific aortic
valve disease (CAVD) is the most common cause of aortic stenosis. There is currently no
medical therapy, except for invasive valve replacement in symptomatic patients, for CAVD. This
is mainly due to poor understanding of pathophysiology, in part due to lack of appropriate
animal models, and lack of appropriate tools for risk stratification and tracking the effect of
interventions in vivo. Beside traditional risk factors, age, gender, tobacco use,
hypercholesterolemia, and hypertension, genetic background is an important determinant of
CAVD. The effect of genetic background is best recognized in bicuspid aortic valve (BAV), the
major cause of advanced CAVD and aortic stenosis in younger subjects. There is ongoing
debate on whether hemodynamic alterations, genetic and cellular factors, or both lead to early
development of CAVD in BAV. Valvular interstitial cell transformation, extracellular matrix
remodeling (including fibrosis) and calcification are pathologic hallmarks of CAVD and play a
central role in its pathogenesis. Several signaling pathways (e.g., Notch) which regulate bone
formation are implicated in the pathogenesis of CAVD, and could potentially serve as targets for
therapeutic interventions aimed at slowing down the progression of the disease. Endothelial and
smooth muscle neuropilin-like protein (ESDN) is a marker of vascular remodeling and regulator
of growth factor signaling in vascular cells. Interestingly, there is a high incidence of BAV
(~50%) in Esdn-/- animals, and in preliminary studies we have observed spontaneous
development of CAVD in aged Esdn-/- mice. These findings will be leveraged to address the
aforementioned gaps in CAVD pathobiology and imaging, by investigating the role of the
neuropilin-like protein, ESDN in experimental calcific aortic valve disease, and to examine the
interplay between leaflet numbers, modifiable risk factors and genetic background in CAVD,
while establishing novel molecular imaging techniques for tracking the effect of interventions
and prediction of outcome in CAVD. These studies will lead to better understating of CAVD
pathophysiology and potentially novel therapeutic targets to mitigate CAVD progression. In
parallel, they will establish novel molecular imaging tools for risk stratification in CAVD with high
potential for clinical translation.

## Key facts

- **NIH application ID:** 9922787
- **Project number:** 5R01HL138567-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** MEHRAN M SADEGHI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $707,264
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922787

## Citation

> US National Institutes of Health, RePORTER application 9922787, Novel Regulators of Calcific Aortic Valve Disease (5R01HL138567-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9922787. Licensed CC0.

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