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 proposal in these ways is aligned with NHLBI's mission of prevention and treatment of CV disease, enhancing the health of all individuals so that they can live longer and more fulfilling lives, and educating the next generation of scientists in the methods applied for this purpose.

Public Health Relevance

Even after surgical correction, patients with coarctation of the aorta (CoA) continue to suffer from a diminished quality of life and a reduced lifespan. We will define the types and extent of vascular changes that occur with this disease using a novel experimental approaches and new molecular mechanisms that allow investigators to study this disease without the additional complications that often exist with CoA clinically. Results from these approaches will be used clinically to propose new criteria for surgeries and long-term treatment of CoA patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Burns, Kristin
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Marquette University
Biomedical Engineering
Biomed Engr/Col Engr/Engr Sta
United States
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