Summary

disease, in angiogenic tumour associated vessels and in aged individuals.Wehavepreviously identifiedanovelanti-inflammatory senescentphenotypeofEC.Weshowherethatcaveolaearecritical in the inductionofthisanti-inflammatorysenescentstate.SenescentEC inducedbyeithertheoverexpressionofARHGAP18/SENEXorbyH2O2 showed significantly increased numbers of caveolae and associated proteins Caveolin-1, cavin-1 and cavin-2. Depletion of these proteins by RNA interference decreased senescence induced by ARHGAP18 and by H2O2. ARHGAP18 overexpression induced a predominantly anti-inflammatory senescentpopulation anddepletionof the caveo-lae-associated proteins resulted in the preferential reduction in this senescent population as measured by neutrophil adhesion and adhesion protein expression after TNFa treatment. In confirmation, EC isolatedfromtheaortasofCAV-1/micefailedto inducethisanti-inflammatory senescent cell population upon expression of ARH-GAP18, whereas EC from wild-type mice showed a significant increase. NF-jB is one of the major transcription factors mediating the induction of E-selectin and VCAM-1 expression, adhesion mole-cules responsible for leucocyte attachment to EC. TNFa-induced activationofNF-jBwassuppressed inARHGAP18-induced senescent EC,andthis inhibitionwasreversedbyCaveolin-1knock-down.Thus, out results demonstrate that an increase in caveolae and its component proteins in senescent ECs is associatedwith inhibition of the NF-kB signalling pathway and promotion of the anti-inflamma-tory senescent pathway. Key words: ARHGAP18; caveolae; cellular senescence; endo-thelial cells; inflammation