GPR43 regulates sodium butyrate-induced angiogenesis and matrix remodeling
GPR43 regulates sodium butyrate-induced angiogenesis and matrix remodeling
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DOI：
10.1152/ajpheart.00515.2019
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发表时间：
2021-03-01
影响因子：
4.8
通讯作者：
Barcelos, Luciola Silva
中科院分区：
文献类型：
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作者：
Castro, Pollyana Ribeiro;Fernandes Bittencourt, Lucas Felipe;Barcelos, Luciola Silva
丁酸是一种源自微生物群的短链脂肪酸 (SCFA)，以浓度依赖性方式参与一系列细胞过程。低浓度的丁酸钠 (NaBu) 被证明具有促血管生成作用。然而，与这些效应相关的机制尚不完全清楚。在这里，我们在缺乏 Gpr43 基因的小鼠 (Gpr43-KO) 和野生型 (WT) 小鼠中使用海绵诱导的纤维血管组织模型研究了 SCFA 受体 GPR43 在 NaBu 局部治疗的促血管生成作用中的贡献及其对基质重塑的影响。我们证明 NaBu（0.2 mM 植入物内）治疗以 GPR43 依赖性方式增强植入物中的新血管形成过程、血流量和 VEGF 水平。此外，除了以 GPR43 依赖性方式增加纤维血管组织中的转化生长因子 (TGF)-β 1 水平外，NaBu 还能够调节肉芽组织的基质重塑方面，例如体内蛋白聚糖的产生、胶原蛋白沉积和 α-平滑肌肌动蛋白 (α-SMA) 表达。有趣的是，NaBu 在体外直接刺激 L929 小鼠成纤维细胞迁移以及 TGF-β1 和胶原蛋白的产生。 GPR43被发现在人真皮成纤维细胞、肌成纤维细胞和内皮细胞中表达。总的来说，我们的研究结果证明，代谢物感应受体 GPR43 有助于低剂量 NaBu 在肉芽组织形成过程中诱导血管生成和基质重塑的作用。这些数据为基于 NaBu 的新治疗方法的提出提供了重要的见解，超越了高度探索的肠道、抗炎和抗癌目的，作为改善组织修复的局部治疗，特别是通过调节肉芽组织成分。新的和值得注意的我们的数据显示了代谢物传感受体 GPR43 在低剂量丁酸钠的作用中的贡献 (NaBu) 在小鼠肉芽组织形成模型中刺激血管生成和细胞外基质重塑。我们还表明，人真皮成纤维细胞、肌成纤维细胞和内皮细胞表达受体 GPR43。这些数据为NaBu在局部治疗方法中的使用提供了重要的见解，该方法适用于肠道以外部位的组织修复。
Butyrate is a short-chain fatty acid (SCFA) derived from microbiota and is involved in a range of cell processes in a concentration-dependent manner. Low concentrations of sodium butyrate (NaBu) were shown to be proangiogenic. However, the mechanisms associated with these effects are not yet fully known. Here, we investigated the contribution of the SCFA receptor GPR43 in the proangiogenic effects of local treatment with NaBu and its effects on matrix remodeling using the sponge-induced fibrovascular tissue model in mice lacking the Gpr43 gene (Gpr43-KO) and the wild-type (WT) mice. We demonstrated that NaBu (0.2 mM intraimplant) treatment enhanced the neovascularization process, blood flow, and VEGF levels in a GPR43-dependent manner in the implants. Moreover, NaBu was able to modulate matrix remodeling aspects of the granulation tissue such as proteoglycan production, collagen deposition, and alpha-smooth muscle actin (alpha-SMA) expression in vivo, besides increasing transforming growth factor (TGF)-beta 1 levels in the fibrovascular tissue, in a GPR43-dependent manner. Interestingly, NaBu directly stimulated L929 murine fibroblast migration and TGF-beta 1 and collagen production in vitro. GPR43 was found to be expressed in human dermal fibroblasts, myofibroblasts, and endothelial cells. Overall, our findings evidence that the metabolite-sensing receptor GPR43 contributes to the effects of low dose of NaBu in inducing angiogenesis and matrix remodeling during granulation tissue formation. These data provide important insights for the proposition of new therapeutic approaches based on NaBu, beyond the highly explored intestinal, anti-inflammatory, and anticancer purposes, as a local treatment to improve tissue repair, particularly, by modulating granulation tissue components.NEW & NOTEWORTHY Our data show the contribution of the metabolite-sensing receptor GPR43 in the effects of low dose of sodium butyrate (NaBu) on stimulating angiogenesis and extracellular matrix remodeling in a model of granulation tissue formation in mice. We also show that human dermal fibroblasts, myofibroblasts, and endothelial cells express the receptor GPR43. These data provide important insights for the use of NaBu in local therapeutic approaches applicable to tissue repair in sites other than the intestine.