Blood Flow and The Mammalian Embryo

Abstract

Hemodynamics, or blood fluid dynamics, is of great importance in vascular biology and its role is well recognized in events ranging from atherosclerosis to wound healing. The importance of hemodynamics during embryonic development, however, is less clear. The early vertebrate vasculature is established through two processes; vasculogenesis, which is the de novo formation of vessels and angiogenesis, which is the sprouting of new vessels from existing vessels and the remodeling of existing vessels. The latter process, angiogenesis and vascular remodeling, is dependent on blood flow and does not occur if cardiac output is blocked. As well, if blood flow is altered, such as with mutations that affect cardiac contraction, the early vessels also fail to remodel. Flowing blood imparts a physical force, called shear stress, on the endothelial lining of the blood vessels. Many genes known to be regulated by shear stress are important for vascular remodeling in the embryo. In this work, we investigate the role of shear stress on the remodeling process. Studying the role of shear stress in embryos requires the ability to measure changes in both fluid dynamics and vascular morphology as well as methods to alter shear stress levels. In this work, we use an optical technique for the quantitative analysis of hemodynamics during early organogenesis in the mouse embryo. We established the morphological changes that occur in the vasculature during remodeling and link these to the fluid dynamics that are present. We establish the mechanical cues that are available to the endothelial cells and the type of flow present at various stages of development. In order to understand how these mechanical cues affect embryonic development, we examine altered shear stress during development using a mutant mouse model in which the atrial cardiac contraction is lacking as well as inducing specific changes in shear stress through chemical manipulation of the embryonic cardiovascular system. These studies establish a link between the pattern of blood flow within the vasculature and the stage of cardiovascular development and enable analysis of the influence of mechanical forces during development.