Wagner Kay-Dietrich, Safwan-Zaiter Hasan, Wagner Nicole
CNRS, INSERM, iBV, Université Côte d'Azur, 06107 Nice, France.
Cells. 2024 Nov 21;13(23):1929. doi: 10.3390/cells13231929.
P16Ink4a is a well-established marker of senescence. Although P16Ink4a is expressed in endothelial cells, little is known about its function in these cells. Using isolated liver endothelial cells with silencing or overexpression of P16Ink4a, we show here that dependent on P16Ink4a levels, different pathways and functions are affected. High levels of P16Ink4a reduce proliferation and induce senescence, while low levels have the opposite effects. Only high P16Ink4a expression reduces in vitro angiogenesis. Expression profiling reveals an inflammatory phenotype upon silencing of P16Ink4a, while P16Ink4a overexpression is associated with a profile associated with DNA damage, repair and senescence. Low levels of P16Ink4a induce reactive oxygen species (ROS) generation and increase endothelial cell leakage. Collectively, P16Ink4a represents an "antagonistic pleiotropy" gene, which is, on the one hand, required to prevent ROS generation and endothelial damage and, on the other hand, inhibits angiogenesis through induction of senescence at high levels.
P16Ink4a是一种公认的衰老标志物。尽管P16Ink4a在内皮细胞中表达，但其在这些细胞中的功能却鲜为人知。通过使用P16Ink4a沉默或过表达的分离肝内皮细胞，我们在此表明，根据P16Ink4a水平的不同，不同的信号通路和功能会受到影响。高水平的P16Ink4a会降低增殖并诱导衰老，而低水平则具有相反的作用。只有高表达的P16Ink4a会降低体外血管生成。表达谱分析显示，P16Ink4a沉默后会出现炎症表型，而P16Ink4a过表达则与DNA损伤、修复和衰老相关的谱型有关。低水平的P16Ink4a会诱导活性氧（ROS）生成并增加内皮细胞渗漏。总的来说，P16Ink4a代表一种“拮抗性多效性”基因，一方面，它是预防ROS生成和内皮损伤所必需的，另一方面，它通过高水平诱导衰老来抑制血管生成。
