Vascular remodelling in the embryo

Vascular remodelling is a process which begins at day 21 of human embryogenesis, when an immature heart begins contracting, pushing fluid through the early vasculature. This first passage of fluid initiates a signal cascade based on physical cues including shear stress and circumferential stress, which is necessary for the remodelling of the vascular network, arterial-venous identity, angiogenesis, and the regulation of genes through mechanotransduction. This embryonic process is necessary for the future stability of the mature vascular network. Vascular remodelling is a process which begins at day 21 of human embryogenesis, when an immature heart begins contracting, pushing fluid through the early vasculature. This first passage of fluid initiates a signal cascade based on physical cues including shear stress and circumferential stress, which is necessary for the remodelling of the vascular network, arterial-venous identity, angiogenesis, and the regulation of genes through mechanotransduction. This embryonic process is necessary for the future stability of the mature vascular network. Vasculogenesis is the initial establishment of the components of the blood vessel network, or vascular tree. This is dictated by genetic factors and has no inherent function other than to lay down the preliminary outline of the circulatory system. Once fluid flow begins, biomechanical and hemodynamic inputs are applied to the system set up by vasculogenesis, and the active remodelling process can begin. Physical cues such as pressure, velocity, flow patterns, and shear stress are known to act on the vascular network in a number of ways, including branching morphogenesis, enlargement of vessels in high-flow areas, angiogenesis, and the development of vein valves. The mechanotransduction of these physical cues to endothelial and smooth muscle cells in the vascular wall can also trigger the promotion or repression of certain genes which are responsible for vasodilation, cell alignment, and other shear stress-mitigating factors. This relationship between genetics and environment is not clearly understood, but researchers are attempting to clarify it by combining reliable genetic techniques, such as genetically-ablated model organisms and tissues, with new technologies developed to measure and track flow patterns, velocity profiles, and pressure fluctuations in vivo. Both in vivo study and modelling are necessary tools to understand this complex process. Vascular remodelling is pertinent to wound healing and proper integration of tissue grafts and organ donations. Promoting an active remodelling process in some cases could help patients recover faster and retain functional use of donated tissues. However, outside of wound healing, chronic vascular remodelling in the adult is often symptomatic of cardiovascular disease. Thus, increased understanding of this biomedical phenomenon could aid in the development of therapeutics or preventative measures to combat diseases such as atherosclerosis. The study of vascular remodelling in the embryo is widely believed to have been pioneered by Thoma in 1893 when he observed that increases in local blood flow cause widening of the vessel diameter, even going so far as to postulate that blood flow might be responsible for the growth and development of blood vessels. Subsequently, Chapman in 1918 discovered that removing a chick embryo’s heart disrupted the remodelling process, but the initial vessel patterns laid down by vasculogenesis remained undisturbed. Next, in 1926 Murray proposed that vessel diameter was proportional to the amount of shear stress at the vessel wall; that is, that vessels actively adapted to flow patterns based on physical cues from the environment, such as shear stress. The chemical basis of morphogenesis,' written in 1952 by mathematician and computer scientist Alan Turing advocated for various biological models based on molecular diffusion of nutrients. However, a diffusive model of vascular development would seem to fall short of the complexity of capillary beds and the interwoven network of arteries and veins. In 2000, Fleury proposed that instead of diffusive molecules bearing responsibility for the branching morphogenesis of the vascular tree, a long-range morphogen may be implicated. In this model, a traveling pressure wave would act upon the vasculature via shear stress to rearrange branches into the lowest-energy configuration by widening vessels carrying increased blood flow and rearranging networks upon the initiation of fluid flow. It is known that mechanical forces can have a dramatic impact on the morphology and complexity of the vascular tree. However, these forces have comparably little impact on the diffusion of nutrients, and it therefore seems unlikely that acquisition of nutrients and oxygen plays a significant role in embryonic vascular remodelling. It is now widely accepted that vascular remodelling in the embryo is a process distinct from vasculogenesis; however these two processes are inextricably linked. Vasculogenesis occurs prior to vascular remodelling, but is a necessary step in the development of the blood vessel network and has implications on the identification of vessels as either arterial or venous. Once contraction of the heart begins, vascular remodelling progresses via the interplay of forces resulting from biomechanical cues and fluid dynamics, which are translated by mechanotransduction to changes at cellular and genetic levels. Vasculogenesis is the formation of early vasculature, which is laid down by genetic factors. Structures called blood islands form in the mesoderm layer of the yolk sac by cellular differentiation of hemangioblasts into endothelial and red blood cells. Next, the capillary plexus forms as endothelial cells migrate outward from blood islands and form a random network of continuous strands. These strands then undergo a process called lumenization, the spontaneous rearrangement of endothelial cells from a solid cord into a hollow tube. Inside the embryo, the dorsal aorta forms and eventually connect the heart to the capillary plexus of the yolk sac. This forms a closed-loop system of rigid endothelial tubing. Even this early in the process of vasculogenesis, before the onset of blood flow, sections of the tube system may express ephrins or neuropilins, genetic markers of arterial or venous identities, respectively. These identities are still somewhat flexible, but the initial characterization is important to the embryonic remodelling process.