Discovering a Rare Smooth Muscle Cell Population Specific to Men in Ascending Aortic Aneurysm Using Spatial Transcriptomics

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 43, No. 12Discovering a Rare Smooth Muscle Cell Population Specific to Men in Ascending Aortic Aneurysm Using Spatial Transcriptomics Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBDiscovering a Rare Smooth Muscle Cell Population Specific to Men in Ascending Aortic Aneurysm Using Spatial Transcriptomics Arif Yurdagul, Jr and Elena Aikawa Arif Yurdagul, JrArif Yurdagul, Jr Correspondence to: Arif Yurdagul Jr, PhD, LSU Health Sciences Center in Shreveport, 1501 Kings Highway, Shreveport, LA 71130. Email E-mail Address: [email protected] https://orcid.org/0000-0002-7613-6313 Department of Molecular and Cellular Physiology, LSU Health Sciences Center in Shreveport, LA (A.Y.). Search for more papers by this author and Elena AikawaElena Aikawa https://orcid.org/0000-0001-7835-2135 Division of Cardiovascular Medicine, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (E.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Division of Cardiovascular Medicine, Department of Medicine, Center for Excellence in Vascular Biology (E.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Search for more papers by this author Originally published2 Nov 2023https://doi.org/10.1161/ATVBAHA.123.320235Arteriosclerosis, Thrombosis, and Vascular Biology. 2023;43:2298–2300This article is a commentary on the followingSingle-Molecule Spatial Transcriptomics of Human Thoracic Aortic Aneurysms Uncovers Calcification-Related CARTPT-Expressing Smooth Muscle CellsOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 2, 2023: Ahead of Print Despite unprecedented advances in cellular and molecular techniques, tissue imaging platforms, and mouse models that recapitulate keys aspects of human diseases, therapies for thoracic aortic aneurysms (TAAs) remain limited to surgical interventions and drug therapy that slows—but does not stop—disease progression.1,2 While TAAs are less common than many other cardiovascular diseases, they are nonetheless extremely life-threatening. In clinical practice, TAAs occur predominantly within the aortic root and ascending aorta, with these regions comprising a majority of the cases.1 Mechanistically, vascular smooth muscle cell (vSMC) death and elastin degradation, features that accompany cystic medial degeneration, drive aortic dilation and aneurysm formation.3 Although our understanding of the mechanisms leading to TAAs (eg, connective tissue disorders,2 hypertension,4 and elevated matrix metalloproteinase activity5) has advanced, there are no pharmacological therapies tailored specifically for this disease.See accompanying article on page 2285To address the need for better medical therapy for TAAs, novel molecular targets have long been under investigation. Why, in an era of cutting-edge scientific advancements, has this been so difficult? A major reason lies in the complexity of the tissue microenvironment. The intricate interplay between vSMCs, extracellular matrix proteins, and various signaling pathways creates a challenging landscape. This is further complicated by genetic heterogeneity, environmental factors, and cardiometabolic comorbidities.2,4–6 However, expansion of advanced transcriptomic and proteomic tools combined with appropriate animal models has renewed optimism that therapeutic breakthroughs are imminent. Because single-cell RNA sequencing (scRNA-seq) can resolve cell heterogeneity within complex tissues, it is often used to capture unbiased transcriptomic signatures in cardiovascular disease, including TAA.7–10 However, due to the abundance, complexity, and cross-linking of aortic matrix components, complete and reproducible enzyme-based dissegregation of cells that is required for scRNA-seq remains technologically challenging. Additionally, preparation of single-cell suspensions—required for scRNA-seq—sacrifices spatial resolution. Because of the complexity of intercellular communication in TAAs, spatial resolution is not just beneficial, it is vital.In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, a groundbreaking study by Mizrak et al11 meets the challenge of identifying aortic cellular transcriptomes while preserving spatial resolution. The authors use multiplexed error-robust fluorescence in situ hybridization, a cutting-edge in situ hybridization technique that couples single-molecule, single-cell transcriptomics with high-resolution spatial imaging, to obtain a more comprehensive view of the molecular basis of ascending aortic aneurysms. Using surgically resected, fresh-frozen ascending aorta specimens from 3 individuals with ascending aortic aneurysm (2 men and 1 woman), as well as aortic specimens from 2 control subjects (1 man and 1 woman), the authors uncover the spatial distribution of rare vSMC subtypes, including a new, spatially distinct subtype distinguished by the expression of CARTPT (CART prepropeptide; Figure). This vSMC subtype is overrepresented in male ascending aorta specimens and is located in areas of calcification, an important observation that was not revealed by scRNA-seq. The authors provide evidence that CART promotes osteochondrogenic phenotypic switching in human vSMCs, suggesting that it stimulates medial calcification (a common feature in ascending aortic aneurysms). This was further supported by the striking overlap between the CARTPT+ vSMC subtype and Alizarin red staining, a finding that would not have been possible with scRNA-seq. Although aneurysms are more common in men, they lead more often to severe outcomes in women.12–14 The emergence and expansion of CARTPT+ vSMCs in men may provide clues that unravel the mechanism of this sexual dimorphism. Nonetheless, it raises an important new question: does CARTPT protect against severe clinical manifestations in males of ascending aortic aneurysms or does is it drive aneurysm initiation or progression? We hypothesize that CART is likely to promote both. As an example, calcification is a common feature of advanced atherosclerosis,15 yet the presence of large, calcific sheets within atheromas are linked to plaque stability,16 whereas spotty calcifications are linked to vulnerable plaques.17,18 Thus, CART may simultaneously promote ascending aortic aneurysm and protect against acute, clinical events. As with most pioneering studies, this work has limitations, including reliance on a small number of samples to support the major conclusions. Nonetheless, the combination of single-molecule, single-cell transcriptomics coupled with spatial resolution is an exciting advance, offering a new, multidimensional view of ascending aortic aneurysm pathogenesis. Hopefully, this study will open new avenues toward targeted medical therapy for ascending aortic aneurysms.Download figureDownload PowerPointFigure. Multiplexed error-robust fluorescence in situ hybridization (MERFISH) reveals a new vascular smooth muscle cell (vSMC) subpopulation in thoracic aortic aneurysm (TAA) in men with evidence suggesting a role in vSMC phenotypic switching. Single-molecule spatial transcriptomics of control and TAA specimens revealed a rare vSMC subpopulation in men, identified by the presence of CARTPT transcripts. CARTPT overexpression or treatment with CART in vSMCs led to the expression of osteochondrogenic transcription factors with a simultaneous decrease in vSMC-exclusive genes. This study demonstrates the feasibility of using single-cell transcriptomic imaging in TAA and unveils a new CARTPT+ vSMC subpopulation that likely plays a role in medial calcification in men. UMAP indicates uniform manifold approximation and projection.ARTICLE INFORMATIONAcknowledgmentsThe Figure was made using BioRender.Sources of FundingA. Yurdagul is supported by the National Institutes of Health (NIH) R00 HL145131 and R01 HL167758; E. Aikawa is supported by the NIH R01 HL136431, R01 HL147095, and R01 HL141917.Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page 2299.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Arif Yurdagul Jr, PhD, LSU Health Sciences Center in Shreveport, 1501 Kings Highway, Shreveport, LA 71130. Email arif.yurdagul@lsuhs.eduREFERENCES1. Isselbacher EM. 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Spotty calcification and plaque vulnerability in vivo: frequency-domain optical coherence tomography analysis.Cardiovasc Diagn Ther. 2014; 4:460–469. doi: 10.3978/j.issn.2223-3652.2014.11.06CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesSingle-Molecule Spatial Transcriptomics of Human Thoracic Aortic Aneurysms Uncovers Calcification-Related CARTPT-Expressing Smooth Muscle CellsDogukan Mizrak, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2023;43:2285-2297 December 2023Vol 43, Issue 12 Advertisement Article Information Metrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.123.320235PMID: 37916413 Originally publishedNovember 2, 2023 KeywordsEditorialsaortic aneurysmaortic diseasescardiovascular diseasesdilatationPDF download Advertisement Subjects Aneurysm Aortic Dissection Atherosclerosis Vascular Disease