KRIT1 is a gene involved in Cerebral Cavernous Malformations (CCMs), a cerebrovascular disease characterized by thin-walled capillaries lacking of normal vessel structure that predispose to headaches, neurological deficits, seizures, stroke and intracerebral hemorrhage (ICH). KRIT1 protein presents a pleiotropic effect, by regulating multiple molecular mechanisms involved in redox homeostasis, angiogenesis, endothelial cellular permeability and alteration of cell-cell and cell- extracellular matrix (ECM) adhesion. The effective correlation between KRIT1 loss- of-function and CCM pathogenesis remains incompletely understood, but experiments in animal models have clearly demonstrated that the homozygous loss of KRIT1 is not sufficient to induce CCM lesions, suggesting that additional factors are necessary to cause CCM disease. We demonstrated that microenvironment lacking KRIT1 protein induces a pro-angiogenic switch of endothelial cells, by increasing endothelial proliferation, migration and MMP-2 production. In order to investigate the molecular mechanisms underlying the endothelial activation promoted by KRIT-/- conditioned media, we found the KRIT1 loss is associated with upregulation of NOX1, COX-2 and VEGF expression level, conversely COX-2 and VEGF levels are significantly reduced after the inhibition of NOX1 activity, demonstrating that NOX1 upregulation in KRIT-/- cells controls both COX-2 and VEGF expression. Finally, we demonstrated that the pro-angiogenic switch of endothelial cells promoted by treatment with KRIT-/- conditioned media was reduced by inhibition of both NOX1 and COX-2 activity, suggesting that KRIT1-loss dependent oxidative stress and inflammation have a key role in the modulation of angiogenic phenotype of HUVEC cells induced. Moreover, we demonstrated that KRIT1 protein is involved in molecular mechanisms that regulate cellular migration, and that this regulation may be mediated by the interaction of KRIT1 with KIF1C, a kinesin family member recently identified as a novel binding partner of KRIT1. Our results contributed to increase the knowledge on the molecular mechanisms underlying the development of vascular alterations observed in CCMs and provide scientific support for the future development of new molecular targets useful in the treatment of CCM.
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|Titolo:||KRIT1 LOSS-OF-FUNCTION INDUCES ANGIOGENESIS AND MIGRATION IN A CCM CELLULAR MODEL|
|Citazione:||Schiavo, I. (2019). KRIT1 LOSS-OF-FUNCTION INDUCES ANGIOGENESIS AND MIGRATION IN A CCM CELLULAR MODEL.|
|Appare nelle tipologie:||8.1 Tesi Dottorato|