title: Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice.
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.
authors.affiliation: Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Tokyo, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tashiro
authors.forename: Chiemi
authors.initials: C
authors.lastname: Nishida
authors.forename: Kaori
authors.initials: K
authors.lastname: Sato-Kusubata
authors.forename: Makiko
authors.initials: M
authors.lastname: Ohki-Koizumi
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishihara
authors.forename: Aki
authors.initials: A
authors.lastname: Sato
authors.forename: Ismael
authors.initials: I
authors.lastname: Gritli
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Komiyama
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Sato
authors.forename: Takashi
authors.initials: T
authors.lastname: Dan
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tomiki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Beate
authors.initials: B
authors.lastname: Heissig
authors.forename: Koichi
authors.initials: K
authors.lastname: Hattori
mesh_terms: D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D012038:Regeneration / Q000187:drug effects* / Q000502:physiology; D058258:Serpin E2 / Q000037:antagonists & inhibitors*; D010959:Tissue Plasminogen Activator / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D062366:para-Aminobenzoates
chemical_list: C549556:5-chloro-2-(((2-(4-(diphenylmethyl)piperazin-1-yl)-2-oxoethoxy)acetyl)amino)benzoate; D043925:Angiogenesis Inducing Agents; D005343:Fibrinolytic Agents; D010879:Piperazines; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D062366:para-Aminobenzoates; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D010129:4-Aminobenzoic Acid