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      Endothelial microRNAs regulating the NF-κB pathway and cell adhesion molecules during inflammation

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      The FASEB Journal
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          Abstract

          The surface of endothelial cells is covered with cell adhesion molecules, including E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM- 1) , that mediate the adhesion and extravasation of leukocytes and play pivotal roles in inflammatory response. microRNAs (miRNAs) regulate the expression of these important cell adhesion molecules through two distinct major mechanisms, namely via modulating the proinflammatory NF-κB pathway, which controls their transcription, and via directly targeting them. The present review highlights the role of various miRNAs in controlling the expression of E-selectin, ICAM-1, and VCAM-1: a type of regulation that can be harnessed for therapeutic prevention of inflammation-associated diseases such as atherosclerosis and sepsis. The roles of secreted miRNAs as paracrine regulators, and cell adhesion molecule-based miRNA delivery are also addressed.-Zhong, L., Simard, M. J., Huot, J. Endothelial microRNAs regulating the NF-κB pathway and cell adhesion molecules during inflammation.

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          Most cited references74

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          Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

          The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.
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            MicroRNAs modulate the angiogenic properties of HUVECs.

            MicroRNAs (miRNAs) have recently come into focus as key posttranscriptional modulators of gene expression. In this work, we addressed whether in vitro angiogenesis is an miRNA-regulated process. We performed large-scale analysis of miRNA expression in human umbilical vein endothelial cells (HUVECs) and found that 15 highly expressed miRNAs have the receptors of angiogenic factors as putative targets. In particular, we demonstrated that miR-221 and miR-222 affect c-Kit expression and, as a consequence, the angiogenic properties of its ligand stem cell factor. Interaction between miR-222 and c-Kit is likely to be part of a complex circuit that controls the ability of endothelial cells to form new capillaries.
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              In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight.

              Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-molecular-weight polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. These nanoparticles mediate the most durable non-liver silencing reported so far and facilitate the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumour growth and metastasis.
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                Author and article information

                Journal
                The FASEB Journal
                The FASEB Journal
                FASEB
                0892-6638
                1530-6860
                August 2018
                August 2018
                : 32
                : 8
                : 4070-4084
                Affiliations
                [1 ]St-Patrick Research Group in Basic Oncology, Centre Hospitalier Universitaire (CHU) de Québec–Université Laval Research Centre (L’Hôtel-Dieu de Québec), Laval University Cancer Research Centre, Québec City, Québec, Canada
                Article
                10.1096/fj.201701536R
                29565737
                08d37d2a-85bc-4fe7-9ed4-1b7d95bbdcb8
                © 2018
                History

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