Chen Dongying, Rukhlenko Oleksii S, Coon Brian G, Joshi Divyesh, Chakraborty Raja, Martin Kathleen A, Kholodenko Boris N, Schwartz Martin A, Simons Michael
bioRxiv. 2024 Jan 25:2024.01.23.576920. doi: 10.1101/2024.01.23.576920.
A key feature of arteriogenesis is capillary-to-arterial endothelial cell fate transition. Although a number of studies in the past two decades suggested this process is driven by VEGF activation of Notch signaling, how arteriogenesis is regulated remains poorly understood. Here we report that arterial specification is mediated by fluid shear stress (FSS) independent of VEGFR2 signaling and that a decline in VEGFR2 signaling is required for arteriogenesis to fully take place. VEGF does not induce arterial fate in capillary ECs and, instead, counteracts FSS-driven capillary-to-arterial cell fate transition. Mechanistically, FSS-driven arterial program involves both Notch-dependent and Notch-independent events. Sox17 is the key mediator of the FSS-induced arterial specification and a target of VEGF-FSS competition. These findings suggest a new paradigm of VEGF-FSS crosstalk coordinating angiogenesis, arteriogenesis and capillary maintenance.
动脉生成的一个关键特征是毛细血管内皮细胞向动脉内皮细胞的命运转变。尽管在过去二十年中，许多研究表明这一过程是由VEGF激活Notch信号驱动的，但动脉生成是如何被调控的仍知之甚少。在此我们报告，动脉特化是由流体剪切力（FSS）介导的，独立于VEGFR2信号，并且VEGFR2信号的下降是动脉生成完全发生所必需的。VEGF不会诱导毛细血管内皮细胞的动脉命运，相反，它会抵消FSS驱动的毛细血管向动脉细胞的命运转变。从机制上讲，FSS驱动的动脉程序涉及Notch依赖性和Notch非依赖性事件。Sox17是FSS诱导的动脉特化的关键介质，也是VEGF-FSS竞争的靶点。这些发现提示了一种VEGF-FSS相互作用协调血管生成、动脉生成和毛细血管维持的新范式。
