# Mechanisms of morbidity after correcting aortic coarctations of varying severity

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $265,339

## Abstract

Project Summary/Abstract
Coarctation of the aorta (CoA) is a congenital cardiovascular (CV) disease characterized by a severe stenosis
of the main artery delivering blood from the heart to the body. CoA affects 5,000 to 8,000 births annually in the
U.S. Treatments exist, but treated CoA patients often have a reduced life expectancy from morbidity, most
notably hypertension (HTN). Identifying the cause of morbidity is difficult because of confounding factors such
as differences in patient age, time to follow-up, severity before treatment, and the presence of other CV
abnormalities. It is also difficult to separate causal genetic contributions that create the initial stenosis from
changes in gene expression due to mechanical consequences after its creation. To remove these barriers we
used RNA sequencing to identify a candidate gene from humans with CoA that had upper extremity systolic
blood pressure (BP) >99th percentile, thereby focusing on mechanical consequences. Natriuretic peptide
receptor 3 (NPR3), a gene known to be associated with BP and cellular proliferation, was downregulated in
sections of the aorta subjected to high BP when compared to normal BP regions. A novel animal model of CoA
was then developed to control for the variability in humans (severity, duration & age), and to study mechanisms
of arterial dysfunction by simulating treatment via absorbable suture. Changes in NPR3 seen in humans with
CoA were replicated with this model. Preliminary data also showed that the current treatment guideline for CoA
permits adverse arterial changes that do not revert after treatment without augmenting NPR3. Evidence is also
provided for new severity and duration treatment thresholds that avoid adverse arterial changes. The current
study uses this model with computational fluid dynamics and associated cell culture analysis to quantify
detailed mechanical stimuli we hypothesize are responsible for arterial remodeling and endothelial dysfunction
in CoA, and eventually lead to HTN. Stimuli are classified according to the structural, functional and cellular
changes they impose using state-of-the-art approaches and specialized agents targeting NPR3. Aim 1 will
confirm the mechanical stimuli that avoids adverse arterial changes by extracting HTN status from clinical
records of CoA patients exposed to the same range of stimuli. Aim 2 will correlate adverse vascular changes
from CoA with NPR3 expression via established pathways with intent to apply existing therapeutics. Aim 3 will
test a novel mechanism for coarctation-induced arterial dysfunction via NPR3 involving myristoylated alanine-
rich C kinase substrate (MARCKS) regulation of phosphoinositide-dependent ion channel and receptor control.
The collective results have the potential for clinical translation in short order by suggesting revised criteria for
when treatment of CoA should be implemented, and identifying targets for management of arterial changes.
Translating results from the current pro...

## Key facts

- **NIH application ID:** 10455296
- **Project number:** 7R01HL142955-05
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** John Frank LaDisa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $265,339
- **Award type:** 7
- **Project period:** 2018-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455296

## Citation

> US National Institutes of Health, RePORTER application 10455296, Mechanisms of morbidity after correcting aortic coarctations of varying severity (7R01HL142955-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10455296. Licensed CC0.

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