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angiogenesis is required for wound healing, its induction   3.  Proteolytic enzymes released by activated endothelial cells
          is  beneficial  in  many  clinical situations  for achieving   dissolve the basement membrane of surrounding parent
          wound closure.                                         vessels;
                                                              4.  Endothelial cells proliferate and sprout outward through
          PHYSIOLOGICAL CONTROL OF                               the basement membrane;
          ANGIOGENESIS                                        5.  Endothelial  cells  migrate into  the  wound  bed using
                                                                 integrins (αvβ3, αvβ5 and αvβ1) which are cell surface
          Angiogenesis  plays a critical role in wound healing. By   adhesion molecules;
          developing capillary sprouts, which digest endothelial   6.  Matrix metalloproteinases (MMPs) dissolve the surrounding
          cells and invade  the  extracellular matrix  (ECM) stroma   tissue matrix in the path of sprouting vessels;
          after  penetrating  through  the  underlying  vascular   7.  Vascular sprouts form tubular channels that connect to
          basement membrane (VBM), and form tube‑like structures   form vascular loops;
          that continue to extend,  branch, and form networks.   8.  Vascular loops differentiate into afferent (arterial) and
          During angiogenesis capillary advancement in ECM occurs   efferent (venous) limbs;
          by endothelial cell  proliferation and direction of growth   9.  New blood vessels mature by recruiting mural cells
          is  guided by  chemotaxis  from  the  target  region.  The   (smooth muscle cells and pericytes) to stabilize the
          interaction  among  endothelial  cells, angiogenesis  factors   vascular architecture;
          and surrounding ECM proteins is temporally and spatially   10.  Blood flow begins in the mature stable vessel.
          synchronized. [9,10]
                                                              These complex growth factor‑receptor, cell‑cell and cell‑matrix
          Angiogenesis can be induced in response to injury via   interactions characterize the angiogenesis process, regardless
          pro‑  and anti‑angiogenic factors present throughout the   of the stimuli or its location in the body.
          body. Pro‑angiogenic factors consist of thrombin, fibrinogen
          fragments,  thymosin‑β4  and  growth  factors.  Angiogenic
          growth factors are stored in platelets and inflammatory   THE ANGIOGENESIS MODEL OF
          cells that circulate in the bloodstream, and are sequestered   WOUND HEALING
          within the ECM. The production of these factors is
          regulated by genes expressed in response to hypoxia and   Wound healing  occurs in  four major  overlapping stages:
          inflammation, such as hypoxia‑inducible factors (HIF) and   (1) hemostatic, (2) inflammatory stage,  (3) proliferative
          cyclooxygenase‑2 (COX‑2). [11‑13]  In contrast, angiogenesis   stage,  and (4) remodeling  stage.  Although granulation
          inhibitor factors suppress blood vessel growth. [14,15]  Some   is  assigned  to the proliferative stage,  angiogenesis  is
          inhibitors circulate in the blood stream at low physiological   initiated  immediately  after tissue  injury and is mediated
          levels while others are stored in the ECM surrounding   throughout the wound healing process.
          blood vessels. Vascular growth is  suppressed  when   Step 1: Angiogenesis initiation
          there  is  a  physiological  balance  between  angiogenesis   Basic fibroblast growth factor (bFGF) stored within intact cells
          stimulators and inhibitors.  Immediately following injury,   and the ECM is released from damaged tissue.  Bleeding and
                                [15]
                                                                                                   [16]
          however, angiogenic stimuli are released into the wound   hemostasis in a wound also initiate angiogenesis. Cellular
          bed, and a shift occurs in regulators favoring vascular   receptors for vascular endothelial growth factor (VEGF) are
          growth [Figure 1].
                                                              upregulated by thrombin in the wound.  Endothelial cells
                                                                                               [17]
                                                              exposed to thrombin also release gelatinase A (MMP‑2), which
          THE ANGIOGENESIS CASCADE                            promotes  the  local  dissolution of basement membrane, a
                                                              necessary early step of angiogenesis.  Platelets release
                                                                                               [18]
          Angiogenesis  occurs as an orderly cascade of molecular   multiple  growth  factors,  including  platelet‑derived
          and cellular events in the wound bed:               growth   factor  (PDGF),  VEGF,  transforming  growth
          1.  Endothelial cell surface has receptors to which angiogenic   factor (TGF‑α, TGF‑β), bFGF, platelet‑derived endothelial
             growth factors bind in preexisting venules (parent vessels);
          2.  Growth factor‑receptor binding activates  signaling   cell growth factor and angiopoietin‑1 (Ang‑1). These factors
                                                              stimulate endothelial proliferation, migration and tube
             pathways within endothelial cells;
                                                              formation. [19‑22]
                                                              Step 2: Angiogenesis amplification
                                                              Macrophages and monocytes release numerous angiogenic
                                                              factors, including PDGF, VEGF, Ang‑1, TGF‑α, bFGF,
                                                              interleukin‑8  (IL‑8) and tumor  necrosis  factor alpha into
                                                              the wound bed during the inflammatory phase amplifying
                                                              angiogenesis further. [23,24]  Several growth factors (PDGF, VEGF
                                                              and bFGF) synergize in their ability to vascularize tissues.
                                                                                                             [25]
                                                              Proteases that break down damaged tissue matrix further
                                                              release  matrix‑bound angiogenic stimulators.  Enzymatic
                                                              cleavage of fibrin yields fibrin fragment E, which
          Figure 1: Angiogenesis is a balance between stimulators (growth factors)
          and inhibitors as shown in this model               stimulates  angiogenesis  directly and also enhances the
           244                                                           Plast Aesthet Res || Vol 2 || Issue 5 || Sep 15, 2015
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