page_title: Vascular remodelling in the embryo
section_title: Mechanotransduction and genetic regulation
hierarchical_section_title: Vascular remodelling in the embryo / Mechanotransduction and genetic regulation
context_page_description: Vascular remodelling is a process which begins usually at day 22, and continues to around the tenth week of human embryogenesis, when, on day 22, an immature heart begins contracting, pushing fluid through the early vasculature. This first passage of fluid initiates a signal cascade and cell movement 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.
context_section_description: The mechanism by which different types of flow patterns and other physical cues have different effects on vascular remodelling in the embryo is called mechanotransduction. Turbulent flow, which is commonplace in the developing vasculature, plays a role in the formation of cardiac valves which prevent backflows associated with turbulence. It has also been shown that heterogeneous flow patterns in large vessels can create asymmetry, perhaps by preferentially activating genes such as PITX2 on one side of the vessel, or perhaps by inducing circumferential stretch on one side, promoting regression on the other side. Laminar flow also has genetic effects, such as reducing apoptosis, inhibiting proliferation, aligning cells in direction of flow, and regulating many cell signalling factors. Mechanotransduction may act either by positive or negative feedback loops, which may activate or repress certain genes to respond to the physical stress or strain placed on the vessel.
  The cell "reads" flow patterns through integrin sensing, receptors which provide a mechanical link between the extracellular matrix and the actin cytoskeleton. This mechanism dictates how a cell will respond to flow patterns and can mediate cell adhesion, which is especially relevant to the sprouting of new vessels. Through the process of mechanotransduction, shear stress can regulate the expression of many different genes. The following examples have been studied in the context of vascular remodelling by biomechanics:
  Endothelial nitric oxide synthase (eNOS), promotes unidirectional flow at the onset of heart beats and is upregulated by shear stress
  Platelet-derived growth factor (PDGF), transforming growth factor beta (TGFβ), and Kruppel-like factor 2 (Klf-2) are induced by shear stress and may have up-regulating effects on genes which deal with endothelial response to turbulent flow
  Shear stress induces phosphorylation of VEGF receptors, which are responsible for vascular development, especially the sprouting of new vessels
  Hypoxia can trigger the expression of hypoxia inducible factor 1 (HIF-1) or VEGF in order to pioneer the growth of new sprouts into oxygen-deprived areas of the embryo
  PDGF-β, VEGFR-2, and connexion43 are upregulated by abnormal flow patterns
  Shear stress upregulates NF-κB, which induces matrix metalloproteinases to trigger the enlargement of blood vessels
  Different flow patterns and their duration can elicit very different responses based on the shear-stress-regulated genes. Both genetic regulation and physical forces are responsible for the process of embryonic vascular remodelling, yet these factors are rarely studied in tandem.,
caption: A feedback model of genetic regulation. In this case the input is a physical force and the feedback can be positive or negative depending on the value of B.