Altered Hemodynamics, Endothelial Function and Protein Expression Occur with Aortic Coarctation and Persist Following Repair
American Journal of Physiology: Gastrointesintal and Liver Physiology, Vol. 303, No. 11 (December 1, 2012): H1304-H1318. DOI.
Abstract
Coarctation of the aorta (CoA) is associated with substantial morbidity despite treatment. Mechanically induced structural and functional vascular changes are implicated; however, their relationship with smooth muscle (SM) phenotypic expression is not fully understood. Using a clinically representative rabbit model of CoA and correction, we quantified mechanical alterations from a 20-mmHg blood pressure (BP) gradient in the thoracic aorta and related the expression of key SM contractile and focal adhesion proteins with remodeling, relaxation, and stiffness. Systolic and mean BP were elevated for CoA rabbits compared with controls leading to remodeling, stiffening, an altered force response, and endothelial dysfunction both proximally and distally. The proximal changes persisted for corrected rabbits despite >12 wk of normal BP (∼4 human years). Computational fluid dynamic simulations revealed reduced wall shear stress (WSS) proximally in CoA compared with control and corrected rabbits. Distally, WSS was markedly increased in CoA rabbits due to a stenotic velocity jet, which has persistent effects as WSS was significantly reduced in corrected rabbits. Immunohistochemistry revealed significantly increased nonmuscle myosin and reduced SM myosin heavy chain expression in the proximal arteries of CoA and corrected rabbits but no differences in SM α-actin, talin, or fibronectin. These findings indicate that CoA can cause alterations in the SM phenotype contributing to structural and functional changes in the proximal arteries that accompany the mechanical stimuli of elevated BP and altered WSS. Importantly, these changes are not reversed upon BP correction and may serve as markers of disease severity, which explains the persistent morbidity observed in CoA patients.