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-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 angiotensin II. Reconstitution of bone marrow-derived cells from Notch1(+/-);Apoe(-/-) mice (donor) in lethally irradiated Apoe(-/-) mice (recipient) decreased the 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. In addition, there was an overall reduction in the inflammatory burden in the aorta of the Notch1(+/-);Apoe(-/-) mice compared with the Apoe(-/-) mice. Last, pharmacological inhibition of Notch1 signaling also prevented AAA formation and progression in Apoe(-/-) mice. CONCLUSIONS: 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.