Type III collagen affects dermal and vascular collagen fibrillogenesis and tissue integrity in a mutant Col3a1 transgenic mouse model

D’hondt, Sanne; Guillemyn, Brecht; Syx, Delfien; Symoens, Sofie; Rycke, Riet De; Vanhoutte, Leen; Toussaint, Wendy; Lambrecht, Bart N.; Paepe, Anne De; Keene, Douglas R.; Ishikawa, Yoshihiro; Bächinger, Hans Peter; Janssens, Sophie; Bertrand, Mathieu J.M.; Malfait, Fransiska

doi:10.1016/j.matbio.2018.03.008

Cited by 58 publications

(62 citation statements)

References 33 publications

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“…Influences of sex in connective tissue homeostasis and disease have been previously recognized. However, most studies indicate that male mice models for connective tissue disorders show more severe phenotypes than female mice [38][39][40][41], which is in contrast to our study.…”

Section: Discussioncontrasting

confidence: 99%

SLC2A knockout mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects

Boel

Burger

Vanhomwegen

et al. 2019

Preprint

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Arterial tortuosity syndrome (ATS) is a recessively inherited connective tissue disorder, mainly characterized by tortuosity and aneurysm formation of the major arteries. ATS is caused by loss-offunction mutations in SLC2A10, encoding the facilitative glucose transporter GLUT10. Former studies implicate GLUT10 in transport of dehydroascorbic acid, the oxidized form of ascorbic acid (AA). Mouse models carrying homozygous Slc2a10 missense mutations do not recapitulate the human phenotype.Since mice, in contrast to humans, are able to intracellularly synthesize AA, we generated a novel ATS mouse model, deficient for Slc2a10 as well as Gulo, which encodes for L-gulonolactone oxidase, an enzyme catalyzing the final step in AA biosynthesis in rodents. Gulo;Slc2a10 knock-out mice show mild phenotypic anomalies, which were absent in single knock-out controls. While Gulo;Slc2a10 knock-out mice do not fully phenocopy human ATS, histological and immunocytochemical analysis revealed compromised extracellular matrix formation. TGFβ signaling remained unaltered, while mitochondrial function was compromised in smooth muscle cells derived from Gulo;Slc2a10 knock-out mice.Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined.

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Section: Discussioncontrasting

confidence: 99%

SLC2A knockout mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects

Boel

Burger

Vanhomwegen

et al. 2019

Preprint

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“…Collagen fibrils within the aortic media showed wide variation in diameter with a generally smaller size when compared to control mice ( Supplementary Fig. 2), consistent with previous reports 2, 8,10 . Fibroblasts within the aortic adventitia of vEDS mice showed gross distension of the endoplasmic reticulum presumably due to impaired trafficking of abnormally folded type III collagen ( Supplementary Fig.…”

supporting

confidence: 91%

“…The presenting signs in the majority of adults with vEDS are vascular dissection or organ rupture, with 25% of patients experiencing a major complication by 20 years of age 1,4 . Little is known about the pathogenesis of this disease and promising treatment strategies remain elusive [5][6][7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

Targetable cellular signaling events drive arterial rupture in knock-in mouse models of vascular Ehlers-Danlos Syndrome

Bowen

Giadrosic

Rykiel

et al. 2019

Preprint

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glycine substitutions in critical residues involved in collagen triple helix assembly (Fig. 1A, B and Supplementary Table 1).Both the Col3a1 G209S/+ and Col3a1 G938D/+ mouse models recapitulate vEDS vascular phenotypes.Mice die suddenly due to aortic rupture, aortic dissection or organ rupture, presenting with hemothorax or hemoperitoneum at necropsy. Col3a1 G938D/+ mice present with a more severe phenotype, with a median survival of 45 days compared to 400 days for the Col3a1 G209S/+ mice, p<0.0001, Fig. 1C-E). Neither mouse model shows a tendency for formation of aortic root or ascending aortic aneurysm, consistent with human phenotypes ( Supplementary Fig. 1).Although the aortic wall architecture is relatively preserved in both models, minor alterations include occasional elastic fiber breaks, decreased aortic wall thickness, and decreased collagen content ( Fig. 1F-I). Analysis by transmission electron microscopy shows disruption of elastic lamellar units including thickened elastic fibers with a moth-eaten appearance, disarray of vascular smooth muscle cells (VSMCs) between fibers, and a paucity of collagen fibrils that normally occupy the intervening space between VSMCs and adjacent elastic fibers ( Supplementary Fig. 2). Collagen fibrils within the aortic media showed wide variation in diameter with a generally smaller size when compared to control mice ( Supplementary Fig. 2), consistent with previous reports 2, 8,10 . Fibroblasts within the aortic adventitia of vEDS mice showed gross distension of the endoplasmic reticulum presumably due to impaired trafficking of abnormally folded type III collagen ( Supplementary Fig. 2).In order to evaluate the effect of drugs previously tested in other models of aortic disease such as Marfan (MFS) and Loeys-Dietz Syndrome (LDS) 11-16 , we assessed the effect of losartan, propranolol, atenolol and amlodipine on survival of vEDS mouse models. Despite all these drugs causing the predicted reduction in blood pressure ( Supplementary Fig. 3), no drugs resulted in increased survival, with losartan, propranolol, and atenolol having no impact, and amlodipine actually increasing the risk of aortic dissection ( Supplementary Fig. 3).We also tested the effect of celiprolol, a b1 antagonist/b2 agonist that previous work has proposed, on the basis of a small trial, to delay adverse events in patients with vEDS 17,18 . Surprisingly, celiprolol, while having the predicted effect on pulse rate, accelerated death from aortic dissection in both the severe Col3a1 G938D/+ and mild Col3a1 G209S/+ vEDS mouse models ( Supplementary Fig. 3). The fact that propranolol, a nonspecific b1/b2 antagonist, and atenolol, a specific b1 antagonist, had no impact on survival, suggest that this deleterious effect does not extend to all b-blockers and may be related to the drug's b2 agonism and/or a2 antagonism 19 .In order to elucidate which signaling abnormalities may mediate disease pathology in vEDS, we performed comparative transcriptional profiling by high-throughput RNA sequencing (RNA-seq) on th...

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“…Surgical management of vascular disease is avoided until impending catastrophe due to operative complications associated with significant morbidity and mortality (3). Little is known about the precise functional consequences of collagen III deficiency in the extracellular matrix, or of the effects that alterations in the extracellular matrix have on intracellular biological processes in this condition, including the potential for nonproductive compensatory responses by neighboring cells that might contribute to disease pathogenesis (4,(14)(15)(16)(17). It is currently unknown if signaling pathways found to be altered in other vascular genetic disorders, such as such as MFS and LDS (18)(19)(20), are also involved in vEDS disease pathogenesis.…”

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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Type III collagen affects dermal and vascular collagen fibrillogenesis and tissue integrity in a mutant Col3a1 transgenic mouse model

Cited by 58 publications

References 33 publications

SLC2A knockout mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects

SLC2A knockout mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects

Targetable cellular signaling events drive arterial rupture in knock-in mouse models of vascular Ehlers-Danlos Syndrome

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

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