Vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase signaling facilitates granulation tissue formation with recruitment of VEGFR1+ cells from bone marrow
Vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase signaling facilitates granulation tissue formation with recruitment of VEGFR1+ cells from bone marrow
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DOI：
10.1007/s12565-017-0424-8
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发表时间：
2018-06-01
影响因子：
1.2
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
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作者：
Park, Keiichi;Amano, Hideki;Majima, Masataka
血管内皮生长因子 (VEGF)-A 促进伤口愈合。 VEGF-A 与 VEGF 受体 1 (VEGFR1) 和 VEGFR2 结合，并通过受体的酪氨酸激酶 (TK) 结构域诱导伤口愈合。在血流恢复和肺再生期间，VEGFR1 的表达升高。然而，伤口愈合的确切机制，尤其是 VEGFR1 上肉芽形成的机制，尚不清楚。我们假设 VEGFR1-TK 信号传导通过促进肉芽组织形成来诱导伤口愈合。通过将海绵盘植入小鼠背部皮下组织中制作手术海绵植入模型。根据海绵的重量和 I 型胶原蛋白免疫组织化学分析的颗粒面积来估计颗粒形成。使用实时 PCR（聚合酶链式反应）根据转化生长因子-β (TGF-β) 和细胞成纤维细胞生长因子-2 (FGF-2) 的表达以及 S100A4 的免疫组织化学分析来估计成纤维细胞标记物的表达。与野生型 (WT) 小鼠相比，VEGFR1 TK 敲除 (TK-/-) 小鼠的肉芽组织形成受到抑制。与WT小鼠相比，VEGFR1 TK-/-小鼠中FGF-2、TGF-β和VEGF-A的表达显着受到抑制，并且肉芽组织中VEGFR1(+)细胞的积累减少。移植绿色荧光蛋白（GFP）转基因WT BM的WT小鼠中源自骨髓（BM）的VEGFR1（+）细胞和S100A4（+）细胞数量高于移植GFP转基因VEGFR1 TK-/- BM的VEGFR1 TK-/-小鼠。这些结果表明，VEGFR1-TK 信号传导诱导了表达 F4/80 和 S100A4 的 BM 衍生 VEGFR1(+) 细胞的积累，并有助于小鼠模型中手术植入的海绵区域周围的肉芽形成。
Vascular endothelial growth factor (VEGF)-A facilitates wound healing. VEGF-A binds to VEGF receptor 1 (VEGFR1) and VEGFR2 and induces wound healing through the receptor's tyrosine kinase (TK) domain. During blood flow recovery and lung regeneration, expression of VEGFR1 is elevated. However, the precise mechanism of wound healing, especially granulation formation on VEGFR1, is not well understood. We hypothesized that VEGFR1-TK signaling induces wound healing by promoting granulation tissue formation. A surgical sponge implantation model was made by implanting a sponge disk into dorsal subcutaneous tissue of mice. Granulation formation was estimated from the weight of the sponge and the granulation area from the immunohistochemical analysis of collagen I. The expression of fibroblast markers was estimated from the expression of transforming growth factor-beta (TGF-beta) and cellular fibroblast growth factor-2 (FGF-2) using real-time PCR (polymerase chain reaction) and from the immunohistochemical analysis of S100A4. VEGFR1 TK knockout (TK-/-) mice exhibited suppressed granulation tissue formation compared to that in wild-type (WT) mice. Expression of FGF-2, TGF-beta, and VEGF-A was significantly suppressed in VEGFR1 TK-/- mice, and the accumulation of VEGFR1(+) cells in granulation tissue was reduced in VEGFR1 TK-/- mice compared to that in WT mice. The numbers of VEGFR1(+) cells and S100A4(+) cells derived from bone marrow (BM) were higher in WT mice transplanted with green fluorescent protein (GFP) transgenic WT BM than in VEGFR1 TK-/- mice transplanted with GFP transgenic VEGFR1 TK-/- BM. These results indicated that VEGFR1-TK signaling induced the accumulation of BM-derived VEGFR1(+) cells expressing F4/80 and S100A4 and contributed to granulation formation around the surgically implanted sponge area in a mouse model.