Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Nat Commun. 2022 Oct 6;13(1):5891. doi: 10.1038/s41467-022-33324-7.
During blood vessel development, endothelial cells become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues. Arterial-venous specification occurs in conjunction with suppression of endothelial cell cycle progression; however, the mechanistic role of cell cycle state is unknown. Herein, using Cdh5-CreER;R26FUCCI2aR reporter mice, we find that venous endothelial cells are enriched for the FUCCI-Negative state (early G1) and BMP signaling, while arterial endothelial cells are enriched for the FUCCI-Red state (late G1) and TGF-β signaling. Furthermore, early G1 state is essential for BMP4-induced venous gene expression, whereas late G1 state is essential for TGF-β1-induced arterial gene expression. Pharmacologically induced cell cycle arrest prevents arterial-venous specification defects in mice with endothelial hyperproliferation. Collectively, our results show that distinct endothelial cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous fate.
在血管发育过程中，内皮细胞被特化成为动脉或静脉命运，以生成一个循环网络，为所有组织提供营养和氧气，并清除代谢废物。动脉-静脉特化发生在抑制内皮细胞周期进程的同时；然而，细胞周期状态的机制作用尚不清楚。在此，我们使用 Cdh5-CreER；R26FUCCI2aR 报告小鼠发现，静脉内皮细胞富含 FUCCI-Negative 状态（早期 G1 期）和 BMP 信号，而动脉内皮细胞富含 FUCCI-Red 状态（晚期 G1 期）和 TGF-β信号。此外，早期 G1 期对于 BMP4 诱导的静脉基因表达是必需的，而晚期 G1 期对于 TGF-β1 诱导的动脉基因表达是必需的。药物诱导的细胞周期阻滞可防止内皮细胞过度增殖小鼠的动脉-静脉特化缺陷。总的来说，我们的结果表明，不同的内皮细胞周期状态为动脉与静脉命运的分子诱导提供了不同的机会窗口。
