Dynamic phenotypes of endothelium: inflammation, angiogenesis and senescence
|演題||Dynamic phenotypes of endothelium: inflammation, angiogenesis and senescence|
|講演者||Prof. Mathew Vadas (Centenary Institute of Cancer Medicine and Cell Biology)|
Endothelial cells exhibit specialisation of phenotypes that can be relatively static reflecting their organ of source (eg venous, arterial, brain, liver etc) or dynamic reflecting the microenvironmental influences. Dynamic phenotypes include complex time-dependent responses such as ones seen to inflammatory stimuli (eg TNF), to angiogenic growth factors or microenvironment, and to ageing.
Angiogenesis induces a major change in the microRNA profile of endothelial cells, and in particular in the 3D environment that is essential for this process. The 3D angiogenic environment induces the rapid loss of a family of microRNAs by an as yet underfined mechanism. The loss of miR-27a in particular is a dominant phenomenon as prevention of this loss inhibits angiogenesis in vitro as well as in vivo. The target of miR-27a includes VE-Cadherin a molecule responsible for the maintenance of functioning endothelial cell junctions. The effect of miR-27a on VE Cadherin is modest in magnitude, but has a major effect on the phenotype. Other lost miRs appear to target different aspects of angiogenesis, for example cell proliferation.
Senescence of endothelial cells is increasingly recognised in pathological states such as atheroma and cancer. A novel gene, we call SENEX (belonging to a RhoGAP-family) induces senescence in endothelial cells by a stress-related pathway that involves p16 and Rb. SENEX is involved in senescence induced by some stimuli such as hypoxia or oxidative stress but not all stress-related pathways nor in replicative senescence. The phenotype of senescent endothelial cells, surprisingly, is anti-inflammatory and there is a repressed response to stimuli such as TNF in terms of leucocyte adhesion and cell surface expression of adhesion proteins. In addition senescence inhibits endothelial permeability. These findings suggest that senescence may have a protective role in vascular biology.
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