Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York] : Elsevier
      Original Publication: New York, Grune & Stratton [etc.]
    • Subject Terms:
      para-Aminobenzoates*; Angiogenesis Inducing Agents/*metabolism ; Neovascularization, Physiologic/*drug effects ; Neutrophils/*drug effects ; Piperazines/*pharmacology ; Regeneration/*drug effects ; Serpin E2/*antagonists & inhibitors; 4-Aminobenzoic Acid/pharmacology ; Animals ; Cells, Cultured ; Drug Evaluation, Preclinical ; Fibrinolytic Agents/pharmacology ; Humans ; Matrix Metalloproteinase 9/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neutrophils/immunology ; Neutrophils/metabolism ; Neutrophils/physiology ; Regeneration/physiology ; Tissue Plasminogen Activator/genetics ; Up-Regulation/drug effects
    • Abstract:
      Plasminogen activator inhibitor-1 (PAI-1), an endogenous inhibitor of a major fibrinolytic factor, tissue-type plasminogen activator, can both promote and inhibit angiogenesis. However, the physiologic role and the precise mechanisms underlying the angiogenic effects of PAI-1 remain unclear. In the present study, we report that pharmacologic inhibition of PAI-1 promoted angiogenesis and prevented tissue necrosis in a mouse model of hind-limb ischemia. Improved tissue regeneration was due to an expansion of circulating and tissue-resident granulocyte-1 marker (Gr-1(+)) neutrophils and to increased release of the angiogenic factor VEGF-A, the hematopoietic growth factor kit ligand, and G-CSF. Immunohistochemical analysis indicated increased amounts of fibroblast growth factor-2 (FGF-2) in ischemic gastrocnemius muscle tissues of PAI-1 inhibitor-treated animals. Ab neutralization and genetic knockout studies indicated that both the improved tissue regeneration and the increase in circulating and ischemic tissue-resident Gr-1(+) neutrophils depended on the activation of tissue-type plasminogen activator and matrix metalloproteinase-9 and on VEGF-A and FGF-2. These results suggest that pharmacologic PAI-1 inhibition activates the proangiogenic FGF-2 and VEGF-A pathways, which orchestrates neutrophil-driven angiogenesis and induces cell-driven revascularization and is therefore a potential therapy for ischemic diseases.
    • Accession Number:
      0 (5-chloro-2-(((2-(4-(diphenylmethyl)piperazin-1-yl)-2-oxoethoxy)acetyl)amino)benzoate)
      0 (Angiogenesis Inducing Agents)
      0 (Fibrinolytic Agents)
      0 (Piperazines)
      0 (Serpin E2)
      0 (Serpine2 protein, mouse)
      0 (para-Aminobenzoates)
      EC 3.4.21.68 (Tissue Plasminogen Activator)
      EC 3.4.24.35 (Matrix Metalloproteinase 9)
      EC 3.4.24.35 (Mmp9 protein, mouse)
      TL2TJE8QTX (4-Aminobenzoic Acid)
    • Publication Date:
      Date Created: 20120511 Date Completed: 20120910 Latest Revision: 20210202
    • Publication Date:
      20250114
    • Accession Number:
      10.1182/blood-2011-12-399659
    • Accession Number:
      22573404