Abstract
Heart valve development is governed by both genetic and biomechanical inputs. Prior work has demonstrated that oscillating shear stress associated with blood flow is required for normal atrioventricular (AV) valve development. Cardiac afterload is defined as the pressure the ventricle must overcome in order to pump blood throughout the circulatory system. In human patients, conditions of high afterload can cause valve pathology. Whether high afterload adversely affects embryonic valve development remains poorly understood. Here we describe a zebrafish model exhibiting increased myocardial afterload, caused by vasopressin, a vasoconstrictive drug. We show that the application of vasopressin reliably produces an increase in afterload without directly acting on cardiac tissue in zebrafish embryos. We have found that increased afterload alters the rate of growth of the cardiac chambers and causes remodeling of cardiomyocytes. Consistent with pathology seen in patients with clinically high afterload, we see defects in both the form and the function of the valve leaflets. Our results suggest that valve defects are due to changes in atrioventricular myocyte signaling, rather than pressure directly acting on the endothelial valve leaflet cells. Cardiac afterload should therefore be considered a biomechanical factor that particularly impacts embryonic valve development.
Highlights
Congenital heart defects (CHD) occur when the heart fails to form appropriately during the early stages of embryonic development
We found no change in the number of ventricular cardiomyocytes between the control and the vasopressin-treated embryos
In order to further determine if increases in loading increased the myocardial cell size or shape, we evaluated cardiomyocytes using rhodamine-labeled phalloidin, which binds actin fibers located predominantly near the cell periphery
Summary
Congenital heart defects (CHD) occur when the heart fails to form appropriately during the early stages of embryonic development. 1.35 million newborns born annually with CHD worldwide [1]. Valve pathology occurs in over 50% of all CHD cases [2]. Only approximately 20% of all CHD arise from a known genetic lesion [3]. Phenotypicallysimilar CHD may arise from mutations in unrelated proteins [4], and identical mutations can cause a variety of distinct phenotypes [5]. A likely explanation of this phenomenon is that the pathology arises from loss or modification of protein function, and through the alteration of the mechanical environment of the heart. Research efforts are directed at defining biomechanical contributions to normal heart development and CHD
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