Blood vessel maturation, which is characterized by the investment of vascular smooth muscle cells (vSMCs) around developing blood vessels, begins when vessels remodel into a hierarchy of proximal arteries and proximal veins that branch into smaller distal capillaries. The ultimate result of maturation is formation of the tunica media-the middlemost layer of a vessel that is composed of vSMCs and acts to control vessel integrity and vascular tone. Though many studies have implicated the role of various signaling molecules in regulating maturation, no studies have determined a role for hemodynamic force in the regulation of maturation in the mouse. In the current study, we provide evidence that a hemodynamic force-dependent mechanism occurs in the mouse because reduced blood flow mouse embryos exhibited a diminished or absent coverage of vSMCs around vessels, and in normal-flow embryos, extent of coverage correlated to the amount of blood flow that vessels were exposed to. We also determine that the cellular mechanism of force-induced maturation was not by promoting vSMC differentiation/proliferation, but instead involved the recruitment of vSMCs away from neighboring low-flow distal capillaries towards high-flow vessels. Finally, we hypothesize that hemodynamic force may regulate expression of specific signaling molecules to control vSMC recruitment to high-flow vessels, as reduction of flow results in the misexpression of Semaphorin 3A, 3F, 3G, and the Notch target gene Hey1, all of which are implicated in controlling vessel maturation. This study reveals another role for hemodynamic force in regulating blood vessel development of the mouse, and opens up a new model to begin elucidating mechanotransduction pathways regulating vascular maturation.

中文翻译：

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在小鼠胚胎发育过程中血管平滑肌细胞募集到血管需要血流动力学力

血管成熟，其特征是血管平滑肌细胞 (vSMCs) 在发育中的血管周围的投资，当血管重塑为近端动脉和近端静脉的层次结构时，就开始了，这些近端静脉分支成较小的远端毛细血管。成熟的最终结果是形成中膜——血管的最中间层，由 vSMC 组成，用于控制血管完整性和血管张力。尽管许多研究表明各种信号分子在调节成熟中的作用，但没有研究确定血液动力学力在调节小鼠成熟中的作用。在目前的研究中，我们提供证据表明，血液动力学力依赖机制在小鼠中发生，因为血流减少的小鼠胚胎表现出血管周围 vSMC 的覆盖减少或缺失，而在正常流动的胚胎中，覆盖程度与血管的血流量相关被暴露了。我们还确定力诱导成熟的细胞机制不是通过促进 vSMC 分化/增殖，而是涉及从邻近的低流量远端毛细血管向高流量血管募集 vSMC。最后，我们假设血流动力学力可能调节特定信号分子的表达以控制 vSMC 募集到高流量血管，因为流量减少导致信号素 3A、3F、3G 和 Notch 靶基因 Hey1 的错误表达，所有这些都与控制血管成熟有关。这项研究揭示了血流动力学力在调节小鼠血管发育中的另一个作用，并开辟了一个新模型，开始阐明调节血管成熟的机械转导途径。