The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS (n = 3) and age-matched non-aneurysmal control tissues from cardiac donors and recipients (n = 4). The expression of key molecules was confirmed by immunostaining. We detected diverse populations of smooth muscle cells (SMCs), fibroblasts, and endothelial cells (ECs) in the aortic wall. Aortic tissues from MFS showed alterations of cell populations with increased de-differentiated proliferative SMCs compared to controls. Furthermore, there was a downregulation of MYOCD and MYH11 in SMCs, and an upregulation of COL1A1/2 in fibroblasts in MFS samples compared to controls. We also examined TGF-β signaling, an important pathway in aortic homeostasis. We found that TGFB1 was significantly upregulated in two fibroblast clusters in MFS tissues. However, TGF-β receptor genes (predominantly TGFBR2) and SMAD genes were downregulated in SMCs, fibroblasts, and ECs in MFS, indicating impairment in TGF-β signaling. In conclusion, despite upregulation of TGFB1, the rest of the canonical TGF-β pathway and mature SMCs were consistently downregulated in MFS, indicating a potential compromise of TGF-β signaling and lack of stimulus for SMC differentiation.

Objective: A cardinal feature of Marfan syndrome is thoracic aortic aneurysm. The contribution of the renin-angiotensin system via AT1aR (Ang II [angiotensin II] receptor type 1a) to thoracic aortic aneurysm progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacological modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on thoracic aortic aneurysm in mice with fibrillin-1 haploinsufficiency ( Fbn1 C1041G/+ ). Approach and Results: Thoracic aortic aneurysm in Fbn1 C1041G/+ mice was found to be strikingly sexual dimorphic. Males displayed aortic dilation over 12 months while aortic dilation in Fbn1 C1041G/+ females did not differ significantly from wild-type mice. To determine the role of AT1aR, Fbn1 C1041G/+ mice that were either +/+ or −/− for AT1aR were generated. AT1aR deletion reduced expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen was administered to male Fbn1 C1041G/+ mice to determine the effects of Ang II depletion. Antisense oligonucleotide against angiotensinogen administration attenuated dilation of the ascending aorta and aortic root and reduced extracellular remodeling. Aortic transcriptome analyses identified potential targets by which inhibition of the renin-angiotensin system reduced aortic dilation in Fbn1 C1041G/+ mice. Conclusions: Deletion of AT1aR or inhibition of Ang II production exerted similar effects in attenuating pathology in the proximal thoracic aorta of male Fbn1 C1041G/+ mice. Inhibition of the renin-angiotensin system attenuated dysregulation of genes within the aorta related to pathology of Fbn1 C1041G/+ mice.

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Background: High frequency ultrasound has facilitated in vivo measurements of murine ascending aortas, allowing aortic strains to be gleaned from two-dimensional images. Thoracic aortic aneurysms associated with mutations in fibrillin-1 (FBN1) display elastin fragmentation, which may impact aortic strain. In this study, we determined the relationship between elastin fragmentation and aortic circumferential strain in wild type and fibrillin-1 hypomorphic (FBN1mgR/mgR) mice. Methods and Results: Luminal diameters of the ascending aorta from wild type and FBN1 hypomorphic (FBN1mgR/mgR) mice were measured in systole and diastole. Expansion of the ascending aorta during systole in male and female wild type mice was 0.21±0.02 mm (16.3%) and 0.21±0.01 mm (17.0%) respectively, while expansion in male and female FBN1mgR/mgR mice was 0.11±0.04 mm (4.9%) and 0.07±0.02 mm (4.5%) respectively. Reduced circumferential strain was observed in FBN1mgR/mgR mice compared to wild type littermates. Elastin fragmentation was inversely correlated to circumferential strain (R^2 = 0.628 p = 0.004) and significantly correlated with aortic diameter. (R^2 = 0.397, p = 0.038 in systole and R^2 = 0.515, p =0.013 in diastole) Conclusions: FBN1mgR/mgR mice had increased aortic diameters, reduced circumferential strain, and increased elastin fragmentation. Elastin fragmentation in FBN1mgR/mgR and their wild type littermates was correlated with reduced circumferential strain.

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Background A robust, accurate, and standardized approach to measurement of the aorta is critical to improve the predictive accuracy of these aortic measurements, and to investigate other aortic imaging biomarkers. Objective Developing a comprehensive and generic schema for characterization of the aorta to enable investigators to standardize data that are collected across all aorta research. Methods A systematic review of the literature was conducted to identify and assess schemata of aortic measurement and description. The schemata were reported and discussed to guide the synthesis of a comprehensive schema. Results We propose the International College of Angiology Aortic Research Schema as a comprehensive design that fills the gaps left behind by previously reported schemata. It is intended to be applicable for all clinically relevant purposes, including endograft development for aneurysm repair and for the accurate characterization of the aortic anatomy. This schema divides the aorta into 14 segments and 2 sections (thoracic and abdominal aortas). The segmentation proposed can be used in addition to specific measurements taken for any aneurysm including the neck, and maximal and minimal diameters of the aneurysm.

In human, pathogenic variants in smad3 are one cause of familial aortopathy. We describe a novel SMAD3 variant of unknown significance (VUS), V244F, in a patient who presented with aortic root dilation, right coronary artery ectasia, abdominal aortic aneurysm, right vertebral artery atresia, and cavernoma. Determination of variant pathogenicity impacted multiple aspects of the patient’s care, including the most appropriate surgical threshold for which to recommend a valve-sparing aortic root replacement. To determine whether the newly identified SMAD3 variant, and whether SMAD3 induced aortopathy in general, can be assayed in a zebrafish embryo model, we injected smad3a mRNA into Tg[kdrl:mCherry] zebrafish embryos. By measuring the size of the dorsal aorta at 48hpf we found a correlation between pathogenic SMAD3 variants and increased dorsal aortic diameter. The newly identified V244F variant increased dorsal aortic diameter (p < 0.0001) similar to that of the pathogenic control variant T261I (p < 0.0084). In addition, we examined several previously identified variants of uncertain significance and found P124T (p < 0.0467), L296P (p < 0.0025) and A349P (p < 0.0056) to behave like T261I. These results demonstrate that the zebrafish embryo assay was successful in validating known pathogenic variants, classifying our newly identified variant V244F as likely pathogenic, and classifying previously identified variants P124T, L296P, and A349P as likely pathogenic. Overall, our findings identify a novel SMAD3 variant that is likely pathogenic as well as offer a new mechanism to model SMAD3 VUSs in vivo.

A 33-year-old man underwent resection of a benign intramural schwannoma of the oesophagus. Similar clinicopathological and immunohistological features prompted a review of an earlier case initially diagnosed as a S-100 negative leiomyosarcoma. This stained positive using a new S-100 immunohistochemical antibody (Dako, Trappes, France). The frequency of these extremely rare tumours may be higher than initially thought. Pitfalls for the surgeon are highlighted and attention is brought to a recent consensus.