Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification.
Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification.
复制标题
DOI：
10.1038/s41467-017-01742-7
复制
发表时间：
2017-12-15
影响因子：
16.6
通讯作者：
Hirschi KK
中科院分区：
文献类型：
--
作者：
Fang JS;Coon BG;Gillis N;Chen Z;Qiu J;Chittenden TW;Burt JM;Schwartz MA;Hirschi KK
在胚胎发育、组织修复和工程中，功能性血管网络的建立是限速的。在血管形成过程中，新生成的内皮细胞迅速扩张成原始丛，其经历血管重塑进入循环网络，需要协调的生长抑制和动脉-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，流体剪切应力，在动脉流量的幅度，最大限度地激活NOTCH信号，上调GJA 4（通常，Cx 37）和下游细胞周期抑制剂CDKN 1B（p27）。这些步骤中的任何一个被阻断都会导致过度增殖和动脉特化的丧失。GJA 4或CDKN 1B的重新表达或化学细胞周期抑制可以恢复内皮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，其中动脉剪切激活NOTCH-GJA 4-CDKN 1B轴，促进内皮细胞周期阻滞，使动脉基因表达。这些见解将指导血管再生和工程。新血管的形成依赖于内皮生物学从增殖到特化表型的严格控制的转换。在这里，Fang等人阐明了这种开关的分子机制，并表明动脉剪切激活Notch-Cx 37-p27轴，促进内皮细胞周期停滞并使动脉基因表达成为可能。
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. New vessel formation relies on a tightly controlled switch in endothelial biology from proliferating to specializing phenotypes. Here, Fang et al. elucidate the molecular mechanisms of this switch and show that the arterial shear activates a Notch-Cx37-p27 axis promoting endothelial cell cycle arrest and enabling arterial gene expression.
登录
查看更多内容
影响因子：
4
作者：
Good, Miranda E.;Nelson, Tasha K.;Burt, Janis M.
通讯作者：
Burt, Janis M.
影响因子：
3.3
作者：
Baeyens N;Schwartz MA
通讯作者：
Schwartz MA
DOI：
10.1083/jcb.201408103
发表时间：
2015-03-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Coon BG;Baeyens N;Han J;Budatha M;Ross TD;Fang JS;Yun S;Thomas JL;Schwartz MA
通讯作者：
Schwartz MA
DOI：
10.1152/ajpheart.00683.2011
发表时间：
2011-11-01
影响因子：
4.8
作者：
Fang, Jennifer S.;Angelov, Stoyan N.;Burt, Janis M.
通讯作者：
Burt, Janis M.
影响因子：
4
作者：
Calder, Ashley;Roth-Albin, Ivana;Draper, Jonathan S.
通讯作者：
Draper, Jonathan S.