A Dual Role of the Senescence Marker P16Ink4a in Liver Endothelial Cell Function.

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.