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

被引:65
作者
Tashiro, Yoshihiko [2 ]
Nishida, Chiemi
Sato-Kusubata, Kaori [3 ]
Ohki-Koizumi, Makiko
Ishihara, Makoto
Sato, Aki
Gritli, Ismael
Komiyama, Hiromitsu [2 ]
Sato, Yayoi
Dan, Takashi [4 ]
Miyata, Toshio [4 ]
Okumura, Ko [5 ]
Tomiki, Yuichi [2 ]
Sakamoto, Kazuhiro [2 ]
Nakauchi, Hiromitsu
Heissig, Beate [3 ,5 ]
Hattori, Koichi [1 ,5 ]
机构
[1] Univ Tokyo, Inst Med Sci, Ctr Stem Cell Biol & Regenerat Med, Minato Ku, Tokyo 1088639, Japan
[2] Juntendo Univ, Fac Med, Dept Coloproctol Surg, Tokyo, Japan
[3] Univ Tokyo, Inst Med Sci, Ctr Stem Cell Biol & Regenerat Med, Dept Stem Cell Dynam, Tokyo 1088639, Japan
[4] Tohoku Univ, Grad Sch Med, United Ctr Adv Res & Translat Med, Sendai, Miyagi 980, Japan
[5] Juntendo Univ, Sch Med, Atopy Allergy Ctr, Tokyo 113, Japan
基金
日本学术振兴会;
关键词
PLASMINOGEN-ACTIVATOR INHIBITOR-1; COLONY-STIMULATING FACTOR; EXPRESSION IN-VIVO; MYOCARDIAL-INFARCTION; GROWTH-FACTOR; TUMOR-GROWTH; G-CSF; ANGIOGENESIS; ISCHEMIA; TYPE-1;
D O I
10.1182/blood-2011-12-399659
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. Abneutralization 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. (Blood. 2012;119(26):6382-6393)
引用
收藏
页码:6382 / 6393
页数:12
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