Elucidating the Mechanical, Structural, Functional, and Molecular Mechanisms Involved in Irreversible Vascular Changes in Aortic Coarctation
Date of Award
Master of Science (MS)
LaDisa, John F.
Coarctation of the aorta (CoA) is a constriction of the thoracic aorta and is one of the most common congenital cardiovascular defects. Treatment by surgical correction has saved the lives of thousands of children, but many still have a reduced lifespan due to hypertension. Previous results using our novel rabbit model showed that the current treatment guideline of a 20 mmHg blood pressure gradient (BPG) induces irreversible vascular changes, which persisted despite correction. Preliminary data of the downregulation of natriuretic peptide receptor C (NPR-C) in proximal aortic tissue of human patients with CoA serves as the possible underlying mechanism for persistent morbidity. The purpose of this investigation was to determine the minimum severity and duration of CoA that causes these persistent vascular changes, and to correlate these changes to NPR-C expression and activity. Rabbits underwent CoA at 10 weeks of age to induce 5, 10, or 20 mmHg BPG severity using permanent or dissolvable sutures, thereby replicating untreated or corrected (i.e. treated) CoA, respectively. Additionally, 21-day and 7-day dissolvable sutures were used in the corrected groups to alter the duration that the CoA is present. Computational fluid dynamics (CFD) simulations using subject-specific control data at 32 weeks were performed on idealized CoA models of each severity to quantify blood pressure (BP), wall tension, and wall shear stress (WSS). Arterial structure and function were evaluated proximal and distal to the CoA, in both aortic as well as carotid and femoral arteries, via histology, immunohistochemistry (IHC), and myograph analysis. These results were then correlated to NPR-C expression and function, assessed with additional IHC and myography. Results revealed that there is a distinct increase in the BP and area of elevated tension in the proximal aorta as the severity of CoA was increased, while in the distal aorta there was a significant increase in the extent and magnitude of elevated WSS. These adverse mechanical stimuli lead to vascular remodeling, significantly less vessel compliance, and severe endothelial dysfunction in the proximal aorta when the BPG was larger than 10 mmHg. An identical threshold in the carotid artery resulted in increased arterial stiffness, while endothelial dysfunction did not occur. Correcting a CoA with a BPG of 10 mmHg or higher within 7 days does prevent significant vascular remodeling and significant loss in vessel compliance, but it does not mitigate endothelial dysfunction. Aortic NPR-C expression is significantly decreased in the presence of CoA, and is not restored following alleviation of a 10 mmHg BPG. The presence of a CoA more severe than 10 mmHg resulted in impaired NPR-C function in all vasculature proximal to the coarctation, but it remains unclear whether alleviation of the CoA restores NPR-C function. Collectively, these results suggest a BPG ≤10 mmHg may be the threshold warranting correction of CoA, which is considerably less than the current clinical treatment guideline of 20 mmHg. Furthermore, preliminary results suggest NPR-C expression and function is reduced and impaired, respectively, due to a CoA more severe than this proposed threshold. This finding suggests NPR-C may be a promising therapeutic target for the vascular adversities involved with CoA and hypertension.
Animal Experimentation and Research Commons, Molecular, Cellular, and Tissue Engineering Commons