Importance of endothelial NF-κB signalling in vascular remodelling and aortic aneurysm formation

Aims Vascular remodeling and aortic aneurysm formation are induced mainly by inflammatory responses in the adventitia and media. However, relatively little is known about the mechanistic significance of endothelium in the pathogenesis of these vascular disorders. The transcription factor nuclear factor-kappa B (NF-κB) regulates the expressions of numerous genes, including those related to pro-inflammatory responses. Therefore, to investigate the roles of endothelial pro-inflammatory responses, we examined the impact of blocking endothelial NF-κB signaling on intimal hyperplasia and aneurysm formation. Methods and Results To block endothelial NF-κB signaling, we used transgenic mice expressing dominant-negative IκBα selectively in endothelial cells (E-DNIκB mice). E-DNIκB mice were protected from the development of cuff injury-induced neointimal formation, in association with suppressed arterial expressions of cellular adhesion molecules, a macrophage marker and inflammatory factors. In addition, blockade of endothelial NF-κB signaling prevented abdominal aortic aneurysm formation in an experimental model, hypercholesterolemic apolipoprotein E-deficient mice with angiotensin II infusion. In this aneurysm model as well, aortic expressions of an adhesion molecule, a macrophage marker and inflammatory factors were suppressed with inhibited expression and activity of matrix metalloproteinases in the aorta. Conclusions Endothelial NF-κB activation up-regulates adhesion molecule expression, which may trigger macrophage infiltration and the inflammation in the adventitia and media. Thus, the endothelium plays important roles in vascular remodeling and aneurysm formation through its intracellular NF-κB signaling.