Evidence map›Paper›PMID 42273728›Full record

ArticleArteriosclerosis, thrombosis, and vascular biology2026

Microfibril Denudation Marks Early Aortic Vulnerability in SMAD3 Variant Carriers: A Multigenerational Study.

Paulina M Kowalewska, Hao Yin, Mofei Wang, Brittany Balint, Sahar Hoveyda, Usha Manian, Pei Jun Zhao, Joshua P Samsoondar, Kevin Yijun Fan, Zengxuan Nong and 7 more

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In one paragraph

Article in Arteriosclerosis, thrombosis, and vascular biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

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4 · The record

Corrections and comments

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5 · Who and what money

Authors and funding

17 authors.

Paulina M Kowalewska *Robarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.ORCID 0000-0003-3231-3020
Hao Yin *Robarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.ORCID 0000-0002-0018-3228
Mofei Wang *Robarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.
Brittany BalintRobarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.ORCID 0000-0002-7520-9509
Sahar HoveydaRobarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.
Usha ManianDepartment of Medicine (Cardiology) (U.M., P.J.Z., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.
Pei Jun ZhaoDepartment of Medicine (Cardiology) (U.M., P.J.Z., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.ORCID 0000-0002-6181-1777
Joshua P SamsoondarRobarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.ORCID 0000-0001-7295-344X
Kevin Yijun FanRobarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.ORCID 0000-0002-8233-5626
Zengxuan NongRobarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.
Caroline O'NeilRobarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.
Matthew T J HareRobarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.ORCID 0009-0008-5613-0863
Julieta LazarteRobarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.ORCID 0000-0002-3637-5467
Sharan GoobieMaritime Medical Genetics Service, IWK Health, Halifax, NS, Canada (S.G.).
Robert A HegeleRobarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.ORCID 0000-0003-2861-5325
Michael W A ChuDepartment of Surgery (M.W.A.C.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.ORCID 0000-0002-9872-399X
J Geoffrey PickeringRobarts Research Institute (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O., M.T.J.H., J.L., R.A.H., J.G.P.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Canada.ORCID 0000-0001-6474-3274

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundIndividuals with Loeys-Dietz syndrome 3 are at risk for thoracic aortic dissection even if their aortas are not substantially dilated. A pathogenic variant of SMAD3 is a genetic trigger, but the cellular programs that underlie the heightened aortic risk remain poorly understood.

methodsWe ascertained the cardiovascular profile of 57 individuals in a 4-generation family with a missense variant in SMAD3 (p.Arg287Gln). Aortic medial architectures were quantified from aortas harvested during thoracic aortic replacement surgery, with 2-dimensional and 3-dimensional profiling of the elastin-microfibril network. TGF-β (transforming growth factor beta)-dependent regulatory networks were investigated by whole-genome RNA sequencing of ascending aortic smooth muscle cells (SMCs) and bioinformatics-informed chromatin immunoprecipitation.

resultsCardiovascular phenotypes of family members harboring the SMAD3 variant included thoracic aortopathy, peripheral artery aneurysms and tortuosity, cerebrovascular disease, coronary artery dissections, and mitral valve prolapse. The median age at the first aortic event was 36.5 years. Ascending aortas were less dilated than the aortic root, with relatively intact lamellar structure and SMC content. However, early pathology was evident, with SMCs separated from elastic lamellae by a thin layer of glycosaminoglycans. Confocal reconstructions revealed that elastic fibers were poorly decorated by microfibrils, with reduced fibrillin-1, fibrillin-2, microfibril associated glycoprotein-2, fibulin-1 and fibulin-2. RNA sequencing of Loeys-Dietz syndrome 3 SMCs revealed reduced microfibril gene expression. Furthermore, PRRX2 (paired related homeobox 2) was found to be downregulated in Loeys-Dietz syndrome 3 SMCs in culture and in situ, occupies gene promoter sites for all 5 microfibrils, and mediates their expression in SMCs. SMAD3 overexpression rescued both

conclusionsThese findings identify SMCs delaminating from unsheathed elastic fibers as an incipient pathological program in Loeys-Dietz syndrome 3 aortas. They also uncover a SMAD3-PRRX2-microfibril axis that, being perturbed, could explain this disconnection phenomenon and contribute to risk.

Indexed as

Aorta, ThoracicAortic Aneurysm, ThoracicAortic DissectionLoeys-Dietz SyndromeMicrofibrilsSmad3 ProteinAneurysm, Ascending AortaAortic Root AneurysmDissection, Ascending AortaDissection, Thoracic AortaElastinFemaleGenetic Predisposition to DiseaseHeredityHeterozygoteHumansElastinSmad3 ProteinSMAD3 protein, humanaorta, thoracicaortic aneurysmelastingene expressionglycosaminoglycansmicrofibrilsmuscle, smooth

Identifiers

PMID42273728
PMCPMC13384375

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