Evidence map›Paper›PMID 40878676›Full record

ArticleCirculation2025

Microvascular Endothelial Cells License APS Vasculopathy Through YAP1- and CCN2-Mediated Signaling.

Hui Shi, Wenying Liang, Zhixia Yang, Claire K Hoy, Qiuyu Wang, Zetao Ding, Haoyu Pan, Yue Shi, Yiran Shen, Cyrus Sarosh and 16 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

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2 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

26 authors.

Hui Shi *Department of Rheumatology and Immunology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (H.S., Z.Y., Z.D., H.P., C.Y.).ORCID 0000-0002-3574-8807
Wenying Liang *Departments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.ORCID 0000-0001-9985-6674
Zhixia Yang *Department of Rheumatology and Immunology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (H.S., Z.Y., Z.D., H.P., C.Y.).
Claire K HoyDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.
Qiuyu WangDepartment of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China (Q.W.).
Zetao DingDepartment of Rheumatology and Immunology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (H.S., Z.Y., Z.D., H.P., C.Y.).ORCID 0009-0006-6949-1700
Haoyu PanDepartment of Rheumatology and Immunology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (H.S., Z.Y., Z.D., H.P., C.Y.).
Yue ShiSchool of Athletic Performance, Shanghai University of Sport, Shanghai, China (Y. Shi).
Yiran ShenDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.ORCID 0000-0002-4220-6862
Cyrus SaroshDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.ORCID 0009-0004-5371-1700
Srilakshmi YalavarthiDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.ORCID 0009-0005-9128-572X
Pooja KapoorDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.
Lucas HudginsDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.ORCID 0009-0002-7850-7250
Caroline E VanceDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.
Rachael WasikowskiDermatology (R.W., L.C.T., J.E.G., A.C.B.), University of Michigan, Ann Arbor, MI.ORCID 0000-0003-3544-3023
Gabriel Figueroa-ParraDepartment of Rheumatology, Mayo Clinic, Rochester, MN (G.F.-P., A.D.-G.).ORCID 0000-0002-6077-8899
Ajay TambralliDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.
Jacqueline A MadisonDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.ORCID 0000-0003-1745-8133
Lam C TsoiDermatology (R.W., L.C.T., J.E.G., A.C.B.), University of Michigan, Ann Arbor, MI.
Johann E GudjonssonDermatology (R.W., L.C.T., J.E.G., A.C.B.), University of Michigan, Ann Arbor, MI.ORCID 0000-0002-0080-0812
Chengde YangDepartment of Rheumatology and Immunology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (H.S., Z.Y., Z.D., H.P., C.Y.).ORCID 0000-0002-3720-634X
Alí Duarte-GarcíaDepartment of Rheumatology, Mayo Clinic, Rochester, MN (G.F.-P., A.D.-G.).
Yu ZuoDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.
Allison C BilliDermatology (R.W., L.C.T., J.E.G., A.C.B.), University of Michigan, Ann Arbor, MI.ORCID 0000-0001-7115-9113
Pei-Suen TsouDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.
Jason S KnightDepartments of Internal Medicine (H.S., W.L., C.K.H., Y. Shen, C.S., S.Y., P.K., L.H., C.E.V., A.T., J.A.M., Y.Z., P.-S.T., J.S.K.), University of Michigan, Ann Arbor, MI.

Funding

University of Michigan Skin Biology and Diseases Resource-based CenterP30AR075043 · NIAMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Johann Eli Gudjonsson · 2019 to 2026
$6.6M
Purinergic modulation of the autoimmune vascular phenotypeR01HL134846 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Jason Knight · 2018 to 2026
$4.8M
Role of the sex biased transcription factor VGLL3 in promoting autoimmune responses in SLER01AI130025 · NIAID · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Johann Eli Gudjonsson · 2017 to 2026
$3.9M
Role of the Hippo pathway in scleroderma pathogenesisR01AI183620 · NIAID · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Johann Eli Gudjonsson, DINESH KHANNA · 2024 to 2026
$1.8M
Thromboinflammatory consequences of infection-induced autoimmunityK08AR080205 · NIAMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Yu Zuo · 2022 to 2026
$865k
NHLBI NIH HHS R01 HL134846NIAID NIH HHS R01 AI130025NIAID NIH HHS R01 AI183620NIAMS NIH HHS K08 AR080205NIAMS NIH HHS P30 AR075043
6 · The paper itself

Abstract

backgroundWhereas antiphospholipid syndrome (APS) is best known for increasing the risk of macrovascular thrombosis, APS vasculopathy is characterized by the abnormal proliferation of endothelial and smooth muscle cells, leading to occlusion of small blood vessels in the skin, kidneys, and heart, among other organs. The underlying mechanisms remain unclear, and targeted treatment options for patients with APS are lacking.

methodsTo identify and analyze APS microvascular endothelial cells (MVECs), skin biopsies of patients with APS complicated by livedo racemosa were characterized using single-cell RNA sequencing. CCN1 (cellular communication network factor 1) and CCN2 were identified in skin and kidney biopsies by immunofluorescence microscopy and in plasma by ELISA. Healthy dermal MVECs were cultured with APS patient-derived serum or immunoglobulin G (IgG), and relevant signaling pathways were characterized using quantitative PCR, immunoblotting, and immunofluorescence microscopy. The proliferation and migration of vascular smooth muscle cells were determined after exposure to conditioned medium from APS IgG-stimulated MVECs. A mouse model of APS IgG-accelerated neointima formation was developed. Anti-CCN2 monoclonal antibodies were tested in vascular smooth muscle cell functional assays and the mouse model.

resultsIncreased endothelial cell expression of CCN1 and CCN2 was identified by single-cell RNA sequencing and further confirmed in APS skin by microscopy as well as in APS plasma by ELISA. Exposure of healthy MVECs to patient IgG triggered the upregulation of CCN1 and CCN2 via Toll-like receptor 4- and YAP1 (yes-associated protein 1)-mediated signaling. CCN2, originating from APS IgG-stimulated MVECs led to the proliferation and migration of vascular smooth muscle cells, phenotypes that were inhibited by an anti-CCN2 antibody or depletion of EGFR (epidermal growth factor receptor). We further observed increased expression of CCN2, along with evidence of YAP1 nuclear translocation, in kidney vessels of APS nephropathy biopsies. Finally, CCN2 inhibition with an anti-CCN2 monoclonal antibody significantly reduced neointima thickening and cell proliferation in a mouse model of APS IgG-accelerated neointima formation.

conclusionsThis study revealed activation of YAP1-mediated signaling in APS dermal microvessels and demonstrated that the YAP1 target CCN2 plays a role in facilitating pro-proliferative communication between MVECs and vascular smooth muscle cells. These findings offer insights into the cellular and molecular mechanisms underlying APS vasculopathy, providing potential therapeutic targets for patients.

Indexed as

Antiphospholipid SyndromeConnective Tissue Growth FactorLivedo ReticularisMicrovesselsNeointimaYAP-Signaling ProteinsAdultAnimalsCase-Control StudiesCell MovementCell ProliferationDisease Models, AnimalEndothelial CellsFemaleGene Expression RegulationGene Knockdown TechniquesCCN2 protein, humanCCN2 protein, mouseConnective Tissue Growth FactorImmunoglobulin GYAP1 protein, humanYap1 protein, mouseYAP-Signaling Proteinsantiphospholipid syndromeconnective tissue growth factorendothelial cellsmicrocirculationneointimavascular smooth muscle cellsYes-associated protein

Identifiers

PMID40878676
PMCPMC12531999

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