Phenotypic switch of vascular smooth muscle cells (VSMCs) plays an important role in the pathogenesis of atherosclerosis. The mRNA expression of the synthetic biomarker Collagen Type I Alpha 1 Chain (COL1A1) gene is upregulated during the switch of VSMCs from the contractile to the synthetic phenotype. The association of noncoding circular RNAs transcribed by the COL1A1 gene with VSMC phenotype alteration and atherogenesis remains unclear. Here we reported a COL1A1 circular RNA (circCOL1A1) which is specifically expressed in VSMCs and is upregulated during phenotype alteration of VSMCs. CircCOL1A1 is also detectable in the serum or plasma. Healthy vascular tissues have a low expression of CircCOL1A1, while it is upregulated in atherosclerosis patients. Through ex vivo and in vitro assays, we found that circCOL1A1 can promote VSMC phenotype switch. Mechanistic analysis showed that circCOL1A1 may exert its function as a competing endogenous RNA of miR-30a-5p. Upregulation of circCOL1A1 ameliorates the inhibitory effect of miR-30a-5p on its target SMAD1, which leads to suppression of transforming growth factor-β (TGF-β) signaling. Our findings demonstrate that circCOL1A1 promotes the phenotype switch of VSMCs through the miR-30a-5p/SMAD1/TGF-β axis and it may serve as a novel marker of atherogenesis or as a therapeutic target for atherosclerosis. All procedures were approved by the Research Ethics Committee of the Renji Hospital (RA-2020–071). All patients included in this research provided written informed consent. The data that support the findings of this study are available from the corresponding author upon reasonable request. Concept and design: L.Z. and X.G. Acquisition of data: M.Y., Q.N., and H.W. Data analysis and interpretation: M.Y., X.G., and H.W. Drafting the manuscript: M.Y. and X.G. Critical revision of the manuscript: Y.Z, G.X., and X.G. Statistical analysis: Y.L., M.Y., X.G., and G.X. Acquisition of funding: Y.L., L.Z., and Q.N. Administrative, technical, and/or material support: Y.W., Y.Y., W.W., S.Y., J.C., L.L., Y.Z., and G.X. ^*,# These authors contributed equally to this study. Received: 22 September 2021 Accepted: 27 August 2022 Article published online: 03 December 2022 © 2022. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Although left innominate vein (LIV) stenosis has been demonstrated to be attributed to compression by adjacent anatomical structures, most of the studies are focusing on hemodialysis patients with clinical symptoms compatible with LIV stenosis. The goal of this study was to retrospectively investigate the incidence of LIV stenosis and its influencing factors in an asymptomatic, non-hemodialysis population, which has rarely been performed. From Jan 2013 to Dec 2014, 212 consecutive cases undergoing a chest multi-detector computed tomography (MDCT) angiography were enrolled. LIV stenosis was defined as loss of the area of the LIV (that is, 1 − compression degree) >25%. Multivariate logistic regression analysis was performed to explore the independent risk factors associated with LIV stenosis. LIV stenosis occurred in 35.4% of cases (75/212), with the median loss of the area of the LIV of 36.2% (interquartile range 30.2–49.8%). There were significant differences in age (62.5 ± 11.7 vs. 58.6 ± 14.3 years; P = 0.041), BMI (23.9 ± 2.9 vs. 23.0 ± 3.3, P = 0.036), the frequency of crossing site of LIV over the origin of the aortic arch (54.7 vs. 24.8%, P < 0.001), and the space between aortic arch and sternum [mean ± SD, 11.6 ± 4.2 mm vs. median, 14.1 (interquartile range 11.9–16.3) mm, P < 0.001] between patients with and without LIV stenosis, but only the latter two were confirmed as independent factors by the multivariate logistic regression analysis [crossing site of LIV over the aortic arch, OR (95% CI) = 2.632 (1.401, 4.944), P = 0.003; space between the aortic arch and sternum, OR (95% CI) = 0.841 (0.770, 0.919), P < 0.001]. The patients with an older age, high BMI, LIV crossing over the origin of the aortic arch, or smaller space between aortic arch and sternum may have high risks for LIV stenosis. They should be paid more attention to exclude LIV stenosis preoperatively using MDCT angiography to prevent venous access dysfunction and symptomatic development by fistula creation when hemodialysis is required.

Background: The development of thoracic aortic dissection (TAD) is closely associated with the loss of vascular smooth muscle cells (VSMCs). Androgen receptor (AR) signaling has increasingly been recognized as an important regulator of cell death in prostate cancer. However, the role of AR signaling in the development of TAD in men remains unknown. Methods: The expression of AR was analyzed in clinical specimens obtained from TAD patients undergoing surgical aortic replacement and control subjects receiving heart transplantation. Using β-aminopropionitrile (BAPN)-induced aortic dissection mouse models, we systematically investigated the protective role of AR through multiple approaches. Histopathological evaluation was performed using immunohistochemistry and immunofluorescence. Primary vascular smooth muscle cells were isolated for functional studies including AR knockdown, ferroptosis assessment, and metabolic profiling. Mechanistic insights were gained through chromatin immunoprecipitation, luciferase reporter assays, and RNA stability tests. Seahorse extracellular flux analysis and targeted metabolomics were employed to characterize metabolic alterations. Results: The expression of AR in VSMCs was downregulated in both clinical samples and animal models of TAD. Using in vitro and in vivo models, we demonstrated a novel function of AR that inhibited ferroptosis in VSMC by promoting excessive lipid peroxidation. Mechanistically, we showed that AR counter-regulated the expression levels of acyl-CoA synthetases ACSL3 and ACSL4 in VSMCs. AR acted as a transcriptional regulator to promote the transcription of ACSL3 gene while inhibiting the transcription of the ACSL4 gene, both of which inhibited lipid peroxidation and ferroptosis. Importantly, activating AR signaling was beneficial in preventing TAD from developing and progressing in the animal model. Conclusions: Our results reveal a previously unrecognized role of AR in TAD pathogenesis and uncover the opposite yet complementary regulation of ACSL3/ACSL4 levels involved in lipid peroxidation-driven ferroptosis in VSMCs.