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

Bowen, Caitlin J.; Giadrosic, Juan Francisco Calderón; Burger, Zachary; Rykiel, Graham; Davis, Elaine C.; Helmers, Mark R.; Benke, Kelly S.; MacFarlane, Elena Gallo; Dietz, Harry C.

doi:10.1172/jci130730

Cited by 46 publications

(71 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is in line with what is observed in humans, patients being heterozygous at the COL3A1 gene, and very rare more syndromic and severe cases with biallelic variants (29). We also confirmed a strong mortality associated with pregnancy and lactation (18,19), and most importantly, a strong sexual difference, underlined by a much higher mortality in male mice than in out of breeding female mice. Such a sexual difference was also observed by Bowen et al in their Col3a1 knock-in model ( 19) echoing the possible excess mortality of young vEDS male patients, as reflected by the slight female predominance in adult cohorts (11).…”

Section: Discussionsupporting

confidence: 91%

“…This observation is coherent with old experiments showing that vessels treated with collagenase are prone to rupture and that wall integrity depends on intact collagen (31).Thinning and collagen content reduction of the adventitia are in line with findings from other vEDS knock-In mouse models (18,19).…”

Section: Discussionsupporting

confidence: 90%

“…sympathetic nervous system could play a deleterious role in our model. Thus, despite that no significant benefit of losartan (at the same daily dose) was obtained by Dietz's group on survival rate of their Col3a1 +/G938D mouse model(19), we firmly believed that the use of AngII receptor antagonist To conclude, the full clinical, biochemical and pharmacological investigation performed in our new vEDS knock-in mouse model showed a sexual difference on survival rate, the presence of thin noninflammatory arteries, a cellular phenotype showing enlarged endoplasmic reticulum and unfolded protein response, and no clear activation of the ERK pathway. The spontaneous occurrence of aortic rupture led to test several anti-hypertensive agents based on the reasoning that any stabilization or decrease in blood pressure would reduce arterial wall stress and improve survival rate.…”

mentioning

confidence: 87%

See 2 more Smart Citations

Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers Danlos syndrome

Legrand

Guery

Faugeroux

et al. 2021

Preprint

View full text Add to dashboard Cite

We created a knock-in Col3a1+/G182R mouse model with spontaneous mortality caused by thoracic aortic rupture that recapitulates a rare vascular genetic disease of type III collagen, the vascular Ehlers-Danlos syndrome (vEDS). Investigation of this model showed lower survival rate in males caused by aortic rupture, thin non-inflammatory arteries and altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1+/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vEDS.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 87%

See 1 more Smart Citation

Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers Danlos syndrome

Legrand

Guery

Faugeroux

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…These mutations interfere with the maturation and deposition of collagen, suggesting that this molecule serves a protective function against catastrophic failure of the aortic wall [ 255 , 269 , 273 ]. Notably, work performed in mouse models of EDS suggests that the protective role of collagen might go beyond its structural function and encompass the indirect regulation of signaling mechanisms that can be targeted pharmacologically to reduce the rate of rupture and death [ 274 ].…”

Section: Genes Associated With Syndromic and Non-syndromic Hereditmentioning

confidence: 99%

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Creamer

Bramel

MacFarlane

2021

Genes

View full text Add to dashboard Cite

Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin–myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.

show abstract

“…Additionally, knocking out a known gene for mcEDS in mice, CHST14 , provided functional evidence for the glycosaminoglycan, dermatan sulfate, in connective tissues 259 . More recently, knock in mice with heterozygous mutations in Col3a1 mimicking patient genetics, revealed abnormal signaling through the PLC/IP3/PKC/ERK pathway and that inhibition of these targets may prevent death due to aortic rupture 260 . Despite TNXB not encoding for collagen or any enzyme involved in collagen modification, it was revealed to play a role in collagen deposition though studies involving inactivation of Tenascin‐X in a murine model of EDS 240 .…”

Section: Molecular Biologymentioning

confidence: 99%

Hypermobile Ehlers‐Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes

Gensemer

Burks

Kautz

et al. 2020

Developmental Dynamics

View full text Add to dashboard Cite

The Ehlers-Danlos syndromes (EDS) are a group of heritable, connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. There is phenotypic and genetic variation among the 13 subtypes. The initial genetic findings on EDS were related to alterations in fibrillar collagen, but the elucidation of the molecular basis of many of the subtypes revealed several genes not involved in collagen biosynthesis or structure. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. hEDS is the most common type of EDS and involves generalized joint hypermobility, musculoskeletal manifestations, and mild skin involvement along with the presence of several comorbid conditions. Variability in the spectrum and severity of symptoms and progression of patient phenotype likely depend on age, gender, lifestyle, and expression domains of the EDS genes during development and postnatal life. In this review, we summarize the current molecular, genetic, epidemiologic, and pathogenetic findings related to EDS with a focus on the hypermobile type.

show abstract

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

Cited by 46 publications

References 64 publications

Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers Danlos syndrome

Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers Danlos syndrome

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

Hypermobile Ehlers‐Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes

Contact Info

Product

Resources

About