Background. Shear stress is an effective modulator of endothelial progenitor cells (EPCs) and has been suggested to play an important role in angiogenesis. The phosphatase and tensin homolog (PTEN)/Akt and guanosine triphosphate cyclohydrolase (GTPCH)/tetrahydrobiopterin (BH4) pathways regulate the function of early EPCs. However, the role of these pathways in the shear stress-induced angiogenesis of late EPCs remains poorly understood. Therefore, we aim to investigate whether shear stress could upregulate the angiogenesis capacity of late EPCs and to further explore the possible underlying mechanisms. Methods. Late EPCs were subjected to laminar shear stress (LSS), and their in vitro migration, proliferation, and tube formation capacity were determined. In addition, the in vivo angiogenesis capacity was explored, along with the expression of molecules involved in the PTEN/Akt and GTPCH/BH4 pathways. Results. LSS elevated the in vitro activities of late EPCs, which were accompanied by downregulated PTEN expression, accelerated Akt phosphorylation, and GTPCH/BH4 pathway activation (all ). Following Akt inhibition, LSS-induced upregulated GTPCH expression, BH4, and NO level of EPCs were suppressed. LSS significantly improved the migration, proliferation, and tube formation ability (15 dyn/cm² LSS vs. stationary: vs. , vs. , and vs. , respectively; all ) along with the in vivo angiogenesis capacity of late EPCs, contributing to the recovery of limb ischemia. These effects were also blocked by Akt inhibition or GTPCH knockdown (, respectively). Conclusions. This study provides the first evidence that shear stress triggers angiogenesis in late EPCs via the PTEN/Akt/GTPCH/BH4 pathway, providing a potential nonpharmacologic therapeutic strategy for promoting angiogenesis in ischemia-related diseases.

中文翻译：

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剪切应力通过 PTEN/Akt/GTPCH/BH4 通路触发晚期内皮祖细胞的血管生成。

背景。剪切应力是内皮祖细胞 (EPC) 的有效调节剂，并且已被认为在血管生成中起重要作用。磷酸酶和张力蛋白同源物 (PTEN)/Akt 和鸟苷三磷酸环水解酶 (GTPCH)/四氢生物蝶呤 (BH4) 通路调节早期 EPC 的功能。然而，这些途径在晚期 EPC 的剪切应力诱导的血管生成中的作用仍然知之甚少。因此，我们旨在研究剪切应力是否可以上调晚期 EPC 的血管生成能力，并进一步探索可能的潜在机制。方法。晚期 EPCs 受到层流剪切应力 (LSS) 的影响，并测定了它们的体外迁移、增殖和管形成能力。除此之外探索了体内血管生成能力，以及参与 PTEN/Akt 和 GTPCH/BH4 通路的分子的表达。结果。LSS 提高了晚期 EPCs的体外活性，伴随着 PTEN 表达下调、Akt 磷酸化加速和 GTPCH/BH4 通路激活（所有）。在 Akt 抑制后，LSS 诱导的上调 GTPCH 表达、BH4 和 EPC 的 NO 水平被抑制。LSS 显着提高了迁移、增殖和管形成能力（15 dyn/cm ² LSS 与固定：对比, 对比,和对比,分别; 全部)以及晚期 EPC的体内血管生成能力，有助于肢体缺血的恢复。这些影响也被 Akt 抑制或 GTPCH 敲低所阻断（，分别）。结论。本研究首次提供了剪切应力通过 PTEN/Akt/GTPCH/BH4 通路触发晚期 EPC 血管生成的证据，为促进缺血相关疾病的血管生成提供了一种潜在的非药物治疗策略。