Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome

MacFarlane, Elena Gallo; Parker, Sarah J.; Shin, Joseph; Kang, Benjamin; Ziegler, Shira G.; Creamer, Tyler J.; Bagirzadeh, Rustam; Bedja, Djahida; Chen, Yi‐Chun; Calderón, Juan F.; Weissler, Katherine; Frischmeyer‐Guerrerio, Pamela A.; Lindsay, Mark E.; Habashi, Jennifer; Dietz, Harry C.

doi:10.1172/jci123547

Cited by 95 publications

(113 citation statements)

References 88 publications

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“…Studies in the Fbn1 mgR/mgR mouse model of Marfan syndrome reveal compromised elastic fiber integrity along the entirety of the aorta, though the greatest losses manifest in the aortic root/ascending aorta where aneurysms first develop [ 68 ]. It has been suggested that the different embryonic lineage of smooth muscle cells in this region (from the second heart field and neural crest) and the different state of mechanical loading (biaxial loading and complex hemodynamics) contribute to the predisposition of the proximal aorta to aneurysm [ 69 – 71 ]. We did not attempt to model propensity due to differential embryonic lineage or site-specific loading.…”

Section: Discussionmentioning

confidence: 99%

Numerical knockouts–In silico assessment of factors predisposing to thoracic aortic aneurysms

Latorre

Humphrey

2020

PLoS Comput Biol

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Myriad risk factors–including uncontrolled hypertension, aging, and diverse genetic mutations–contribute to the development and enlargement of thoracic aortic aneurysms. Detailed analyses of clinical data and longitudinal studies of murine models continue to provide insight into the natural history of these potentially lethal conditions. Yet, because of the co-existence of multiple risk factors in most cases, it has been difficult to isolate individual effects of the many different factors or to understand how they act in combination. In this paper, we use a data-informed computational model of the initiation and progression of thoracic aortic aneurysms to contrast key predisposing risk factors both in isolation and in combination; these factors include localized losses of elastic fiber integrity, aberrant collagen remodeling, reduced smooth muscle contractility, and dysfunctional mechanosensing or mechanoregulation of extracellular matrix along with superimposed hypertension and aortic aging. In most cases, mild-to-severe localized losses in cellular function or matrix integrity give rise to varying degrees of local dilatations of the thoracic aorta, with enlargement typically exacerbated in cases wherein predisposing risk factors co-exist. The simulations suggest, for the first time, that effects of compromised smooth muscle contractility are more important in terms of dysfunctional mechanosensing and mechanoregulation of matrix than in vessel-level control of diameter and, furthermore, that dysfunctional mechanobiological control can yield lesions comparable to those in cases of compromised elastic fiber integrity. Particularly concerning, therefore, is that loss of constituents such as fibrillin-1, as in Marfan syndrome, can compromise both elastic fiber integrity and mechanosensing.

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Section: Discussionmentioning

confidence: 99%

Numerical knockouts–In silico assessment of factors predisposing to thoracic aortic aneurysms

Latorre

Humphrey

2020

PLoS Comput Biol

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“…Blood pressure reduction is ineffective in improving survival of vEDS mouse models. In order to evaluate the effect of blood pressure reduction on prevention of vascular rupture in vEDS mouse models, we assessed the effects of losartan, propranolol, atenolol, and amlodipine, all drugs previously tested in MFS and LDS mouse models and known to reduce systemic blood pressure in mice (6,8,(18)(19)(20)27). Despite all of these drugs causing the predicted reduction in blood pressure (Supplemental Figure 4), no treatment resulted in increased survival, with losartan, propranolol, and atenolol having no impact, and amlodipine trending toward an increased risk of aortic rupture (Supplemental Figure 4).…”

Section: Introductionmentioning

confidence: 99%

Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome

Bowen¹,

Giadrosic²,

Burger³

et al. 2019

Journal of Clinical Investigation

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“…Lineage-tracing experiments in mice have shown that there is a significant area of overlap between these lineages at the base of the aorta (Harmon and Nakano, 2013;Sawada et al, 2017). Indeed, it has been suggested that the differential response to cytokines and/or ECM composition between these overlapping or adjacent VSMC populations underpins the origins of aortic aneurysm and dissection (Topouzis and Majesky, 1996;Cheung et al, 2012), an hypothesis supported by recent work in mice (Angelov et al, 2017;MacFarlane et al, 2019). Tgfbr2 deletion in VSMCs led to the development of thoracic aortic aneurysms, whereas treatment with a TGF-β neutralizing antibody resulted in abdominal aortic aneurysms (Angelov et al, 2017).…”

Section: Lineagesmentioning

confidence: 92%

Aortic “Disease-in-a-Dish”: Mechanistic Insights and Drug Development Using iPSC-Based Disease Modeling

Davaapil

Shetty

Sinha

2020

Front. Cell Dev. Biol.

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Thoracic aortic diseases, whether sporadic or due to a genetic disorder such as Marfan syndrome, lack effective medical therapies, with limited translation of treatments that are highly successful in mouse models into the clinic. Patient-derived induced pluripotent stem cells (iPSCs) offer the opportunity to establish new human models of aortic diseases. Here we review the power and potential of these systems to identify cellular and molecular mechanisms underlying disease and discuss recent advances, such as gene editing, and smooth muscle cell embryonic lineage. In particular, we discuss the practical aspects of vascular smooth muscle cell derivation and characterization, and provide our personal insights into the challenges and limitations of this approach. Future applications, such as genotype-phenotype association, drug screening, and precision medicine are discussed. We propose that iPSC-derived aortic disease models could guide future clinical trials via "clinical-trials-in-a-dish", thus paving the way for new and improved therapies for patients.

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Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome

Cited by 95 publications

References 88 publications

Numerical knockouts–In silico assessment of factors predisposing to thoracic aortic aneurysms

Numerical knockouts–In silico assessment of factors predisposing to thoracic aortic aneurysms

Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome

Aortic “Disease-in-a-Dish”: Mechanistic Insights and Drug Development Using iPSC-Based Disease Modeling

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