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Funding Acknowledgements Type of funding sources: None. Background Intracranial aneurysm (IA) rupture is a common cause of hemorrhagic stroke. IAs are present in 3 to 5% of the general population and the annual rupture rate of an IA has been estimated to 1%. Once formed, an IA can rupture immediately, grow before rupturing, or remain stable. Predicting the evolution of an unruptured IA is very difficult. Indeed, the biology of the IA wall is complex and the precise biomechanical processes leading to aneurysm wall rupture are not yet known. While the contribution of wall shear stress in IA disease has been demonstrated in several studies, the role of cyclic circumferential stretch (CCS) remains poorly understood. Purpose The levels of CCS in saccular IAs are unknown but are generally considered very low or even absent. The goal of our study was to investigate the transcriptional response of endothelial cells (ECs) to absence of CCS and the potential impact on the endothelium function. Methods Human umbilical veins ECs (HUVECs) from 6 different donors were exposed to physiological CCS levels for cerebral arteries (6% stretch) or to aneurysmal CCS (0%) for 48h using the Flexcell strain unit FX-5000T, and unbiased transcriptomics were performed. The expression of selected genes was confirmed by qPCR. Results As a validation of our methodology, we verified the induction of eNOS phosphorylation after exposure of the ECs to physiological CCS. Stretched EC samples display a high similarity between each other while EC samples under aneurysmal CCS were spread-out on a multidimensional scaling plot. The differential gene expression of ECs exposed to aneurysmal or physiological CCS revealed 51 up-regulated genes and 49 down-regulated genes in absence of CCS. The gene set enrichment analysis identified 70 up-regulated and 38 down-regulated pathways in HUVECs exposed to aneurysmal CCS. Up-regulated pathways were involved in oxidative stress, angiogenic and inflammatory pathways, and the down-regulated pathways in proliferation and extracellular matrix-receptor interactions. We confirmed by qPCR the down-regulation by aneurysmal CCS of Gja4 and Gja5, genes coding for the gap junction proteins Connexin37 (Cx37) and Connexin40 (Cx40), respectively. Connexins (Cxs) are crucial proteins for endothelial homeostasis, vascular function, endothelial cell cycle regulation and inflammation, and their role in the context of IA disease will be further studied. Conclusion Our results indicate that physiological CCS prevents large deviation in ECs and regulate the expression of genes essential for maintaining vascular homeostasis. The down-regulation of endothelial Cx37 and Cx40 under aneurysmal CSS may contribute to the endothelial dysfunction associated with IA progression. Further investigation may help to better define the role of Cxs in aneurysmal disease and to understand the significance of absence of CCS in IA disease progression. [ABSTRACT FROM AUTHOR]