Impaired vascular smooth muscle cell force-generating capacity and phenotypic deregulation in Marfan Syndrome mice

Nolasco, Patrícia; Fernandes, Carolina Gonçalves; Ribeiro-Silva, João Carlos; Oliveira, Percíllia; Sacrini, Mariana; Brito, Isis Vasconcelos de; Bessa, Tiphany De; Pereira, Lygia V.; Tanaka, Leonardo Yuji; Alencar, Adriano M.; Laurindo, Francisco Rafael Martins

doi:10.1016/j.bbadis.2019.165587

Cited by 32 publications

(32 citation statements)

References 59 publications

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“…Furthermore, vascular smooth muscle cells of MFS mice demonstrated a phenotype switch to mesenchymal-like cells, which resulted in impaired traction forces and a dampened force response to stiffer substrates. 39 This further affirms the plasticity of the cells in the thoracic wall and its contributions to vascular disease.…”

Section: Genetic Syndromessupporting

confidence: 52%

Bio-chemo-mechanics of the thoracic aorta

2021

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The pathophysiology of thoracic aortic aneurysms and dissections are poorly understood, despite high mortality associated with the diseases. An evidence review was conducted to examine the biomechanical, chemical and genetic factors involved in thoracic aortic pathology. The composition of connective tissue and smooth muscle cell action can mediate important mechanical properties that allow the thoracic aorta to withstand and transmit pressures. Genetic syndromes can affect connective tissue and signalling proteins that interrupt smooth muscle function, leading to tissue failure. There are complex interplaying factors that maintain thoracic aortic function in health and disrupt in disease, signifying an area for extensive research.

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Section: Genetic Syndromessupporting

confidence: 52%

Bio-chemo-mechanics of the thoracic aorta

2021

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“…We have suggested that the propensity of TAAs to form in cases of either fibrillin-1 mutations or smooth muscle cell dysfunction, among others, points to the mechanotransduction axis as a potential initiator of these lesions [ 6 ]. Recent studies in cells and different genetically modified mice support this hypothesis [ 80 , 83 – 85 ]. This in silico study is the first, however, to examine mechanosensing in isolation.…”

Section: Discussionmentioning

confidence: 94%

“…Smooth muscle cell-induced vasoconstriction also enables the aortic wall to resist distension under the action of blood pressure. Multiple mutations predisposing to TAAs, including those encoding fibrillin-1 and fibulin-4 and especially those encoding smooth muscle α-actin and smooth muscle myosin heavy chain, compromise vessel-level contractility [ 16 , 52 , 79 , 80 ]. Some have thus implied that loss of vessel-level contractility predisposes to TAAs, yet smooth muscle contractility is also compromised in cases wherein TAAs do not develop, including fibulin 5 null mice [ 81 ].…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, despite some suggestions to the contrary, our simulations suggest that localized losses in vessel-level contractility need not be strong initiators of TAAs. Toward this end, we emphasize that cell-level contractility [ 80 ] is controlled by the same actomyosin regulators as is vessel-level contractility [ 52 ], with cell-level manifestations affecting both cell migration and the mechanosensing and mechanoregulation of matrix.…”

Section: Discussionmentioning

confidence: 99%

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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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“…However, some other recently known risk factors require further investigation. [1][2][3][4][5][6][7][8] There are few studies about aortic aneurysm that look at immunological issues and the results of these studies are controversial. In addition, these studies involve only a small number of patients and are of limited significance.…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressive Agents and Thoracic Aortic Aneurysm: Real Correlation or Mere Coincidence?

Ostovar

Laux

Kuehnel

et al. 2021

Thorac Cardiovasc Surg

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Background Atherosclerosis, hypertension, age, and fibrillopathies are well-known risk factors for the development of aortic aneurysm. We discovered that a significant proportion of our patients were previously on chemotherapy treatment or long-term treatment with cytostatic agents or immunosuppressive drugs. Thus, we examined this phenomenon. Methods A total of 224 patients with thoracic aorta aneurysm were retrospectively analyzed after aortic surgery from 2006 to 2016. Seventy-three patients received aortic wrapping and 151 patients underwent aortic replacement of which 89 had a valve-carrying conduit and 62 a supracoronary ascending replacement. Aortic morphology was assessed by means of compute tomography scan before and after surgery. Demographic data, risk profile, and postoperative complications were collected. Short- and long-term survival analysis was performed. Statistical analysis was performed with SPSS 19.0. Results Eighty-eight of 224 patients undergoing aortic surgery because of aortic aneurysm had previously or currently been treated with immunosuppressive agents. Dilatation of the ascending aorta was more pronounced in patients without such therapy. Demographic profile, intraoperative, as well as short- and long-term postoperative results did not differ significantly between both groups. Conclusion The potential effect of immunosuppressant and cytostatic therapies on the development of an aortic aneurysm needs further study. Because of the astoundingly high proportion of these patients being found in an unselected aortic aneurysm cohort with immunosuppressive therapy in the past should be monitored for potential development of aortic aneurysm. If it occurs and requires treatment these patients can fortunately be operated upon with the same short- and long-term outcome than patients without such previous therapy.

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Impaired vascular smooth muscle cell force-generating capacity and phenotypic deregulation in Marfan Syndrome mice

Cited by 32 publications

References 59 publications

Bio-chemo-mechanics of the thoracic aorta

Bio-chemo-mechanics of the thoracic aorta

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

Immunosuppressive Agents and Thoracic Aortic Aneurysm: Real Correlation or Mere Coincidence?

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