Page 15 - Read Online
P. 15

effects of VEGF and bFGF.  Expression  of the inducible   140 amino  acids.  Acidic FGF and  bFGF are  the  first  few
                                [26]
          COX‑2  enzyme  during  the  inflammatory  stage  of  healing   to be discovered and  are now designated as FGF‑1 and
          also leads to VEGF production and other promoters of   FGF‑2,  respectively.   Both are  preferentially  involved
                                                                               [42]
          angiogenesis. [27]                                  in  the  process of angiogenesis. [43,44]   These  compounds
                                                              are polypeptides of about 18  kDa, single chained and
          Step 3: Vascular proliferation                      nonglycosylated. They transmit their signals through
          Hypoxia is an important driving force for wound
          angiogenesis.  Expression  of gene  HIF‑1α,  due to hypoxic   FGF  receptor‑4 (FGFR‑4) high‑affinity, protein family of
          gradient between  injured and healthy tissue  triggers   transmembrane  tyrosine  kinases  (FGFR‑1 to FGFR‑4), that
          VEGF production. [24,28]  VEGF is present  in both wound   bind to different FGFs with different affinities. The strong
          tissue and exudate. [28,29]  VEGF is also known as vascular   interactions of FGF‑1 and FGF‑2 with glycosaminoglycans,
                                                                                                    [45]
          permeability factor  since it increases permeability of   such as heparin sulfate present in the ECM,  makes the
          capillaries.  Hypoxia also leads to endothelial cell   FGFs stable against thermal, proteolytic denaturation and
                   [30]
          production of nitric oxide (NO). NO promotes vasodilation   limits its diffusibility. Thus, the ECM acts as a reservoir for
          and angiogenesis to improve local blood flow. [31]  pro‑angiogenic  factors. Most  members  of the  FGF family
                                                              act as a broad spectrum mitogen  that stimulates  the
          Step 4: Vascular stabilization                      proliferation of mesenchymal cells of mesodermal origin,
          Vascular stabilization is governed by Ang‑1, tyrosine kinase   as well as ectodermal and endodermal cells.
          with immunoglobulin‑like and EGF‑like domains 2 (Tie‑2),
          smooth  muscle cells and pericytes.  Production of PDGF   FGF‑1 and FGF‑2 are synthesized by a variety of cell types
          and recruitment of smooth muscle cells and pericytes to   including inflammatory cells and dermal fibroblasts that
          the newly forming vasculature are regulated by binding   are involved in angiogenesis  and wound healing.  When
          of Ang‑1 to its  receptor Tie‑2 on activated endothelial   liberated from ECM,  they act on the endothelial cells
          cells. [32‑34]  A PDGF deficiency leads to poorly‑formed   in  a  paracrine  manner,  or when  released  by  endothelial
          immature blood vessels. [35]                        cell they act in an autocrine manner promoting cell
                                                              proliferation and differentiation.  During the formation of
          Step 5: Angiogenesis suppression                    granulation tissue, FGF‑2 promotes cell migration through
          Angiogenesis  is suppressed  at  the  terminal  stages  of   surface receptors for integrins, which mediate the binding
          healing.  As tissue hypoxia is restored, and inflammation   of endothelial cells to ECM. [44]
                [36]
          subsides, the level of growth factors decline in the wound.   Vascular endothelial growth factor increase vaso‑permeability
          Pericytes which stabilize endothelial cells secrete an   by  increasing  the  fenestration  and  hydraulic  conductivity.
          inhibitory form of activated TGF‑β that impedes vascular
          proliferation. [34,37,38]   A  cleavage product of collagen XVIII,   This  allows leakage  of fibrinogen  and fibronectin,
          endostatin, is present surrounding the VBM, and it inhibits   which are essential for the formation of the provisional
                                                                   [46‑48]
          wound vascularity. [39,40]                          ECM.     The ECM is produced  in large quantities  by
                                                              the  epidermis  during wound healing.  Low oxygen
                                                                                                 [49]
          WOUND ANGIOGENIC STIMULATORS                        tension  that occurs in tissue  hypoxia is  a major inducer
                                                              of  VEGF   and its  receptors.   Thus,  cell disruption  and
                                                                                       [51]
                                                                     [50]
          AND INHIBITORS                                      hypoxia appear to be strong initial  inducers of potent
                                                              angiogenesis  factors at the wound site.  VEGF family
          A number of angiogenic stimulators have been  identified   currently includes VEGF‑A,  VEGF‑B, VEGF‑C,  VEGF‑D,
          in wound sand others are likely to exist that play an   VEGF‑E and placental growth factor.  VEGF‑A is a
                                                                                                [52]
          important role in the  repair [Table 1]. The stimulators   homodimer  glycoprotein  whose  subunits  are  linked by
          in wound fluids are growth factors known to increase   2  disulfide  bonds.  VEGF‑A  is  synthesized  from  internal
          endothelial cell migration and proliferation in vitro. [41]  rearrangements  (“alternative splicing”) of mRNA.  Thus,
          The FGF comprises of 23  homologous structures that   there is the production of 7 isoforms with 121  to 206
          are small polypeptides with a central core containing   amino  acids. [53‑55]   Among  these,  the  VEGF121,  VEGF165,
                                                              VEGF189 and VEGF206 are  the  predominant  isoforms.
                                                                                                             [56]
          Table 1: Angiogenic stimulators and inhibitors      These isoforms show similar biological activities, but differ
                                                                                                      [57]
           Stimulators     Inhibitors                         in their binding properties to heparin and ECM.
                                                              Vascular  endothelial  growth  factor  is  a  potent  vascular
           aFGF (FGF-1)    Thrombospondin-1
           bFGF (FGF-2)    Tissue inhibitors of matrix metalloproteinases  endothelial cell‑specific mitogen that stimulates endothelial
           TGF‑α           Interferon alpha/beta/gamma        cell proliferation, microvascular permeability and  regulates
           TGF‑β           Angiostatin                        of several endothelial integrin receptors during sprouting
                                                                                  [58]
           PGE2            Endostatin                         of new blood vessels.  Furthermore, VEGF also acts
           TNF‑α                                              as a survival  factor  for  endothelial  cells by inducing the
           VEGF                                               expression of an anti‑apoptotic protein B‑cell lymphoma 2. [59]
           EGF
                                                              TGF‑β stimulates the formation of granulation tissue by
           FGF:  Fibroblast  growth  factor,  aFGF:  Acidic  fibroblast  growth  factor,   acting as a chemoattractant for neutrophils, macrophages
           bFGF: Basic fibroblast growth factor, TGF‑α: Transforming growth factor‑alpha,
           TGF‑β: Transforming growth factor‑beta, VEGF: Vascular endothelial growth   and fibroblasts. Hence, TGF‑β is an important modulator
           factor, EGF: Endothelial growth factor, PGE2: Prostaglandin E2  of angiogenesis  during  wound  healing  by  regulating  cell
          Plast Aesthet Res || Vol 2 || Issue 5 || Sep 15, 2015                                             245
   10   11   12   13   14   15   16   17   18   19   20