MTOR inhibition prevents angiotensin II-induced aortic rupture and pseudoaneurysm but promotes dissection in Apoe-deficient mice.

George Tellides,Martin A Schwartz,Mo Wang,Pengwei Ren,Changshun He,Bo Jiang,Alexander W Caulk,Roland Assi,Guangxin Li,Lingfeng Qin,Constantinos J Lovoulos,Jay D Humphrey,Sae-Il Murtada

doi:10.1172/jci.insight.155815

Abstract

Aortic dissection and rupture are triggered by decreased vascular wall strength and/or increased mechanical loads. We investigated the role of mTOR signaling in aortopathy using a well-described model of angiotensin II–induced dissection, aneurysm, or rupture of the suprarenal abdominal aorta in Apoe-deficient mice. Although not widely appreciated, nonlethal hemorrhagic lesions present as pseudoaneurysms without significant dissection in this model. Angiotensin II–induced aortic tears result in free rupture, contained rupture with subadventitial hematoma (forming pseudoaneurysms), dilatation, or healing, while the media invariably thickens regardless of mural tears. Medial thickening results from smooth muscle cell hypertrophy and extracellular matrix accumulation, including matricellular proteins. Angiotensin II activates mTOR signaling in vascular wall cells, and inhibition of mTOR signaling by rapamycin prevents aortic rupture but promotes dissection. Decreased aortic rupture correlates with decreased inflammation and metalloproteinase expression, whereas extensive dissection correlates with induction of matricellular proteins that modulate adhesion of vascular cells. Thus, mTOR activation in vascular wall cells determines whether aortic tears progress to dissection or rupture. Previous mechanistic studies of aortic aneurysm and dissection by angiotensin II in Apoe-deficient mice should be reinterpreted as clinically relevant to pseudoaneurysms, and mTOR inhibition for aortic disease should be explored with caution.

Highlights

The aorta serves as the primary conduit for conveying blood from the heart to the body, and its wall consists of 3 functionally distinct layers, the intima, media, and adventitia
Continuous high-rate infusion of angiotensin II (AngII) for up to 7 days frequently led to aortic tears, adventitial containment of hematomas, with minimal or no dissection, and associated pseudoaneurysm, but seldom led to transmural rupture with associated hemorrhagic mortality and never caused, in 42 infused adult male Apoe–/– mice, isolated true dissection of the aorta
AngII-induced aortic disease in Apoe–/– mice was first interpreted as abdominal aortic aneurysm based on external expansion of the lesion [9], noting that the term aneurysm derives from the Greek ανευρυσμα, meaning “a widening.”

Summary

Introduction

The aorta serves as the primary conduit for conveying blood from the heart to the body, and its wall consists of 3 functionally distinct layers, the intima, media, and adventitia. Rupture is a tear through the aortic wall, resulting in extramedial hemorrhage that is either contained by the adventitia and/or surrounding tissues or extravasated with free accumulation within body cavities. Intimal tears extending into the media but without blood between medial lamellae give rise to aortic wall defects considered a variant form of dissection that contribute to aneurysm formation [2]. These lesions, termed incomplete dissection or limited intimal tears, may expose the adventitia if the media is completely disrupted [3]. The initial description of limited dissection considered the lesion along a spectrum of mural lacerations involving varying depths of the vascular wall, ranging from classic dissection to partial and transmural rupture [4]

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Conclusion