{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:21:45Z","timestamp":1791235305924,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"18","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Whereas 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>To 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\u2013derived 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\u2013stimulated MVECs. A mouse model of APS IgG\u2013accelerated neointima formation was developed. Anti-CCN2 monoclonal antibodies were tested in vascular smooth muscle cell functional assays and the mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Increased 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\u2013 and YAP1 (yes-associated protein 1)\u2013mediated signaling. CCN2, originating from APS IgG\u2013stimulated 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\u2013accelerated neointima formation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>This 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.073552","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T09:00:15Z","timestamp":1756458015000},"page":"1295-1310","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["Microvascular Endothelial Cells License APS Vasculopathy Through YAP1- and CCN2-Mediated Signaling"],"prefix":"10.1161","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3574-8807","authenticated-orcid":true,"given":"Hui","family":"Shi","sequence":"first","affiliation":[{"name":"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.)."},{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9985-6674","authenticated-orcid":true,"given":"Wenying","family":"Liang","sequence":"additional","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixia","family":"Yang","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire K.","family":"Hoy","sequence":"additional","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China (Q.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6949-1700","authenticated-orcid":true,"given":"Zetao","family":"Ding","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Pan","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Shi","sequence":"additional","affiliation":[{"name":"School of Athletic Performance, Shanghai University of Sport, Shanghai, China (Y. 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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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9128-572X","authenticated-orcid":true,"given":"Srilakshmi","family":"Yalavarthi","sequence":"additional","affiliation":[{"name":"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."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Kapoor","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (H.S., W.L., C.K.H., Y. 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