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MECHANISM OF WOUND HEALING - Coggle Diagram

- - - - Phase 4: Remodeling (maturation, contraction)
        
        • Begins approximately 3 to 4 weeks after injury, only after the inflammation and proliferation phases have been successfully completed.
        • Can last for 2 or more years.
        • Includes the remodeling of granulation tissue and the maturation of connective tissue.
        • Tissues need time to return to the near-normal tensile strength for normal axial and appendicular skeletal function.
      - • Can last up to 3 to 4 weeks long depending on the size of wound.
        • Migration of basal cells in tissues lined by epithelium.
        • The migrating basal cells proliferate, spread to bridge the wound, and some will differentiate (differentiation will cause them to cease to proliferate and migrate).
        • Characterized by angiogenesis, epithelization and fibroplasia/desmoplasia to restore normal structure and function of the injured tissue.
        • Example: healing of the skin after third-degree burns or severe ulcerations.
        • Depends on the retention of normal stromal elements of the ECM to provide the structural framework for repair, and normally functioning fbroblasts, myofbroblasts (contractile fbroblasts), endothelial cells, pericytes (nonendothelial components of blood vessels), and epithelial cells.
        • Mesenchymal stromal cells subjacent to epithelia also undergo proliferation and communicate between epithelial cells and the subjacent inﬂammatory cells and stroma (the mesenchymal stromal cells function similarly to those of embryonic blastema cells).
- - - - • Migration of endothelial cells into wounds under the autocrine inﬂuence of HIFα and EGF which enhance expression of genes that improve cell survival in hypoxic conditions.
        • Growth factors such as PDGF, FGF, VEGFA, angiogenins, and ephrins released from macrophages, endothelial cells, and fibroblasts.
        • VEGF A and its various isoforms stimulate the initial stages of endothelial cell proliferation.
        • Proliferative eﬀects of VEGF are regulated by Notch ligands and receptors.
        • VEGF enhances expression of DII4, a ligand in vascular tip cells produced by tip cells that bind to Notch receptors expressed by stalk cells.
        • DII4 binding of Notch receptor leads to expression of genes by the stalk cells that reduce VEGFR expression and cellular proliferation.
        • The secondary stages of endothelial cell proliferation involve angiopoietin 1 and its receptor, Tie2, both of which establish vascular stabilization through the recruitment of pericytes and smooth muscle cells and deposition of ECM proteins.
        • Vascular stabilization is further advanced by PDGF and TGFβ.
    - - • Newly formed endothelial cells and fibroblasts migrate into wound sites and bind to fibrinogen and plasma proteins.
        • Mediated by adhesion molecules like α5 and β3integrins, expressed by new endothelial cells and fibroblasts.
        • For wound repair, enhancement of angiogenesis is beneficial and vital.
        • In neoplasia, inhibition of angiogenesis and thus the growth of the tumor have potential therapeutic benefits.
    - - • Once blood vessels are initially formed, they are loosely arranged and require remodeling to become mature.
        • Produce a mature basement membrane.
        • Smooth muscle cells and pericytes can form within the wall.
        • Fibroblasts can form adventitial fibers, depending on whether the vessel is a capillary, artery, vein, or lymphatic vessel.
        • Other endothelial cell growth factors and receptors involved with vascular remodeling include angiopoietin 2, which also binds Tie2 and ephrin B2 (EphB2) and its receptor, EphB4.
        • Proliferation of lymphatic endothelial cells is mediated largely by VEGFC and its receptor, VEGFR3, as well as prox 1 gene expression.
    - - • Produced by endothelial cells, macrophages, and fibroblasts.
        • Balance the proliferative healing responses of angiogenesis.
        • Prevent overexuberant proliferation of endothelial cells.
        • Include angiostatin, endostatin, thrombospondin, and specialized CXC chemokines.
        • Certain isoforms of VEGF can bind VEGF receptors and reduce VEGF signaling and activity.
        • Has potential chemotherapeutic role against certain types of cancer and for exuberant vascularization like those that can occur in the retina.