# Differential Shear Forces on Endocardial Endothelial Cells Regulate a Fibrotic Spectrum in the Left Ventricular Outflow Tract

> **NIH NIH R01** · RICE UNIVERSITY · 2020 · $530,145

## Abstract

PROJECT SUMMARY
Discrete subaortic stenosis (DSS) is a congenital or acquired condition that accounts for ~10% of all
cases of left ventricular outflow tract (LVOT) obstruction, and is characterized by a ring of fibrous tissue
below the aortic valve. Current treatment is surgical removal of the obstruction, but the unpredictable
recurrence and progression of DSS leads to multiple repeat surgeries and attendant morbidity into
adulthood. Current theories postulate that altered LVOT geometry causes increased shear stress and
ultimately fibrosis in DSS; however, little is known about the mechanism of DSS progression. Studies in
vascular endothelial cells demonstrated increased inflammation and phenotypic changes in response to
altered shear forces, but effects of shear are under-studied in endocardial endothelial cells (EEC).
Additionally, resident fibroblasts are implicated in organ fibrosis, including cardiac tissue, in response to
altered cytokine signaling and mechanical forces. We hypothesize that that altered shear forces induce
an inflammatory response by EEC, which interacts with cardiac fibroblasts (CF) to govern a fibrotic
phenotype that contributes to the pathophysiology of DSS, which we will address with three specific aims.
AIM 1. Elucidate the mechanisms of how shear forces regulate EEC inflammatory phenotype.First, we
shall utilize patient echo data and computational modeling to develop a bioreactor that resembles altered flows
in DSS. Using this innovative system, we will then test the role of CD-31 mechanosensory signaling in EEC in
response to altered shear forces and geometry. Lastly, we shall investigate the effects of altered shear forces
on EEC interactions with inflammatory cells in propagating a pro-inflammatory environment.
AIM 2. Determine EEC transduction of altered shear forces to govern fibrosis in the LVOT. We shall
investigate EEC propensity towards endoMT in response to simulated DSS altered shear and immune
cell interactions. We shall then investigate the direct and inflammatory-mediated effects of EEC
mechanosensing on CF that produce a fibrotic ECM. Lastly, we shall study the effect of the stiffer
environment induced by fibrosis on EEC-CF crosstalk, which may propagate the fibrotic response.
AIM 3. Characterize the aggressive DSS phenotype using patient data to develop a predictive model. We
shall first evaluate the ECM composition, remodeling profile and echo data that characterizes the aggressive
forms of DSS in humans. We shall then use these data to develop a multivariate computational model that can
be used to predict an aggressive phenotype, which will be validated and tested.
This proposal will improve the care of children with DSS. With completion of these aims, innovative
tools and new knowledge will emerge about the effects of shear force on EEC-CF and EEC-immune cell
cross-talk. These findings have potential implications for any cardiovascular disease with altered flow
associated with fibrosis.

## Key facts

- **NIH application ID:** 9929012
- **Project number:** 5R01HL140305-03
- **Recipient organization:** RICE UNIVERSITY
- **Principal Investigator:** KATHRYN JANE GRANDE-ALLEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $530,145
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929012

## Citation

> US National Institutes of Health, RePORTER application 9929012, Differential Shear Forces on Endocardial Endothelial Cells Regulate a Fibrotic Spectrum in the Left Ventricular Outflow Tract (5R01HL140305-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9929012. Licensed CC0.

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