Author ORCID Identifier

https://orcid.org/0000-0002-2893-1523

Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Physiology

First Advisor

Dr. Alan Daugherty

Abstract

Thoracic aortic aneurysms (TAAs) are clinically-silent dilations of the aorta which greatly increase the risk of aortic rupture, a condition with 50-90% mortality. Marfan syndrome (MFS) is caused by mutations in fibrillin-1 (FBN1) and is associated with TAAs. Due to an absence of validated and effective pharmacologic therapies to prevent or reverse TAA, most MFS patients require surgical aortic repair. Understanding MFS associated TAA pathogenesis would direct development of new pharmacologic therapies. Previous research has implicated the renin angiotensin system in TAA. In both males and females, angiotensinogen (AGT) is cleaved serially to generate the main effector peptide angiotensin II (AngII). AngII is the main ligand of AngII receptor type 1a (AT1aR). However, the role of angiotensin II (AngII) receptor type 1a (AT1aR) in MFS associated TAA formation is unclear. Here, we test the hypothesis that AngII-dependent AT1aR stimulation is responsible for Marfan syndrome associated TAA.

To study the contribution of the renin angiotensin system on MFS associated TAA, we used the fibrillin-1 haploinsufficient (Fbn1C1041G/+) and fibrillin-1 hypomorphic (Fbn1mgR/mgR) mouse models. TAA in MFS mice demonstrated sexual dimorphism. Compared to male Fbn1C1041G/+ mice, female Fbn1C1041G/+ mice exhibited less ascending aortic dilation. To study AT1aR in MFS associated TAA, we bred male and female AT1aR deficient (AT1aR‑/‑) x Fbn1C1041G/+ mice. We measured the ascending aorta up to 12 months of age by high frequency ultrasound sequentially. We evaluated aortic medial structure at study termination. Compared to male AT1aR+/+ x Fbn1C1041G/+ mice, male AT1aR‑/‑ x Fbn1C1041G/+ mice exhibited less ascending aortic dilation and reduced elastin fragmentation. Ascending aortic dilation was not significant between female AT1aR‑/‑ x Fbn1C1041G/+ mice and female AT1aR+/+ x Fbn1C1041G/+ mice. To study the contribution of angiotensin peptides, we administered angiotensinogen antisense oligonucleotides (AGT ASO) to male Fbn1C1041G/+ mice. Compared to male Fbn1C1041G/+ mice administered control ASO, mice administered AGT ASO exhibited less ascending aortic dilation and reduced elastin fragmentation.

TAA in the mouse models of MFS is sexually dimorphic. Inhibition of the renin angiotensin system via either AT1aR deletion or AGT ASO is sufficient to attenuate ascending aortic dilation in male Fbn1C1041G/+ mice. However, the effect of AT1aR deletion was not detectable in female Fbn1C1041G/+ mice. Depletion of angiotensin ligands was efficacious in attenuating MFS associated TAA in male Fbn1C1041G/+ mice. However, factors that impact TAA of other etiologies have minimal impact on MFS associated TAA. These studies indicate that modulating the renin angiotensin system is highly effective to attenuate MFS associated TAA in males.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.352

Funding Information

The authors' research work is supported by the American Heart Association Strategically Focused Research Network in Vascular Disease (18SFRN33960163) from 2018-present and the National Institutes of Health National Heart, Lung, and Blood Institute under award number R01HL133723 from 2016-2019 to Dr. Alan Daugherty. Jeff Chen has been supported by National Center for Advancing Translational Sciences UL1TR001998 from 2018-2019 and by National Heart, Lung, and Blood Institute F30143943 from 2019-present. The content in this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the American Heart Association or the National Institutes of Health.

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