Department of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
Yale Cardiovascular Research Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
Nat Commun. 2017 Dec 15;8(1):2149. doi: 10.1038/s41467-017-01742-7.
Establishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering.
功能性血管网络的建立在胚胎发育、组织修复和工程中受到限制。在血管形成过程中，新生成的内皮细胞迅速扩展为原始丛，这些丛经历血管重塑成为循环网络，这需要协调的生长抑制和动静脉特化。控制内皮细胞周期停滞和获得特化表型的机制是否相互依赖尚不清楚。在这里，我们证明了动脉流量大小的流体切应力最大程度地激活了 NOTCH 信号通路，该信号通路上调了 GJA4（通常为 Cx37）和下游细胞周期抑制剂 CDKN1B（p27）。阻断这些步骤中的任何一个都会导致过度增殖和动脉特化的丧失。GJA4 或 CDKN1B 的重新表达，或化学细胞周期抑制，可恢复内皮细胞的生长控制和动脉基因表达。因此，我们阐明了一个机械化学途径，其中动脉切应力激活 NOTCH-GJA4-CDKN1B 轴，促进内皮细胞周期停滞，从而实现动脉基因表达。这些见解将指导血管再生和工程。
