Inhibition of Notch1 Signaling Reduces Abdominal Aortic Aneurysm in Mice by Attenuating Macrophage-Mediated Inflammation

Abstract

Objective Activation of inflammatory pathways plays a critical role in the development of abdominal aortic aneurysms (AAA). Notch1 signaling is a significant regulator of the inflammatory response; however, its role in AAA is unknown. Methods and Results In an angiotensin II (AngII)-induced mouse model of AAA, activation of Notch1 signaling was observed in the aortic aneurysmal tissue of Apoe−/− mice and a similar activation of Notch1 was observed in aneurysms of humans undergoing AAA repair. Notch1 haploinsufficiency significantly reduced the incidence of AAA in Apoe−/− mice in response to AngII. Reconstitution of bone marrow-derived cells from Notch1+/−; Apoe−/− mice (donor) in lethally irradiated Apoe−/− mice (recipient) decreased occurrence of aneurysm. Flow cytometry and immunohistochemistry demonstrated that Notch1 haploinsufficiency prevented the influx of inflammatory macrophages at the aneurysmal site by causing defects in macrophage migration and proliferation. Additionally, there was an overall reduction in the inflammatory burden in the aorta of the Notch1+/−;Apoe−/− mice as compared to the Apoe−/− mice. Lastly, pharmacologic inhibition of Notch1 signaling also prevented AAA formation and progression in Apoe−/− mice. Conclusion Our data suggest that decreased levels of Notch1 protect against the formation of AAA by preventing macrophage recruitment and attenuating the inflammatory response in the aorta.

Notch signaling mediated by TGF-β/Smad pathway in concanavalin A-induced liver fibrosis in rats

“…Growing evidence shows that Notch signaling plays a crucial role in the pathogenesis of multiple inflammatory diseases[16,17]. Our findings of increased activation of Notch signaling are consistent with ConA-induced liver fibrosis.…”

AT1 receptor signaling pathways in the cardiovascular system

“…In addition, activation of Notch1 signaling is observed in AngII-induced abdominal aortic aneurysm (AAA). AAA formation induced by AngII is attenuated by Notch1 haploinsufficiency via modulation of macrophage infiltration or inflammatory activation (147). AngII-induced AAA formation and vascular inflammation is also attenuated by pharmacological inhibition of Notch signaling (148).…”

Macrophages in vascular inflammation – From atherosclerosis to vasculitis

“…As a drug, a dexamethasone prodrug can effectively impair macrophage infiltration although its mechanism is not fully understood (134). In addition, Notch1, tumor necrosis factor receptor-associated factor 1, and thrombospondin-1 are reported to be involved in the recruitment of macrophages and might provide elegant options to target macrophage-dependent pathology (63, 135, 136). However, therapeutic strategies targeting macrophage recruitment also need to accommodate their potential harmful side resulting from the disruption of housekeeping functions of macrophages in vascular tissues.…”