Endothelial-to-mesenchymal transition primes vascular endothelial cells toward an osteochondrogenic fate.
| Title: | Endothelial-to-mesenchymal transition primes vascular endothelial cells toward an osteochondrogenic fate. |
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| Authors: | Kishta F; Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH16 4TJ, UK.; Hall IF; Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH16 4TJ, UK.; Li G; Department of Pathology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht 6229ER, the Netherlands.; Tripathi T; Center for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4UU, UK.; Vermeren M; Center for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4UU, UK.; Cholewa-Waclaw J; Center for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4UU, UK.; Rossi F; Center for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4UU, UK.; Péault BM; Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH16 4TJ, UK; Department of Orthopedic Surgery and Orthopedic Hospital Research Center, University of California, Los Angeles, CA 90095, USA.; Rodor J; Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH16 4TJ, UK.; Beqqali A; Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH16 4TJ, UK.; Sluimer JC; Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH16 4TJ, UK; Department of Pathology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht 6229ER, the Netherlands; Department of Medicine 2 (Nephrology, Clinical Immunology, Rheumatology, Hypertension), RWTH Aachen University, Medical Faculty, Aachen 52074, Germany.; Crisan M; Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH16 4TJ, UK; Center for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4UU, UK. Electronic address: Mihaela.Crisan@ed.ac.uk.; Baker AH; Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH16 4TJ, UK; Department of Pathology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht 6229ER, the Netherlands. Electronic address: Andy.Baker@ed.ac.uk. |
| Source: | Vascular pharmacology [Vascul Pharmacol] 2026 Mar; Vol. 162, pp. 107579. Date of Electronic Publication: 2025 Dec 29. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Science Country of Publication: United States NLM ID: 101130615 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-3649 (Electronic) Linking ISSN: 15371891 NLM ISO Abbreviation: Vascul Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York, NY : Elsevier Science, c2002- |
| MeSH Terms: | Human Umbilical Vein Endothelial Cells*/metabolism ; Human Umbilical Vein Endothelial Cells*/pathology ; Human Umbilical Vein Endothelial Cells*/drug effects ; Osteogenesis*/drug effects ; Mesenchymal Stem Cells*/metabolism ; Mesenchymal Stem Cells*/pathology ; Mesenchymal Stem Cells*/drug effects ; Chondrogenesis*/drug effects ; Atherosclerosis*/pathology ; Atherosclerosis*/metabolism ; Atherosclerosis*/genetics ; Vascular Calcification*/pathology ; Vascular Calcification*/metabolism ; Vascular Calcification*/genetics ; Aortic Diseases*/pathology ; Aortic Diseases*/metabolism ; Aortic Diseases*/genetics; Endoglin/metabolism ; Endoglin/genetics ; Animals ; Humans ; Disease Models, Animal ; Cells, Cultured ; Cell Differentiation ; Mice, Inbred C57BL ; Cell Lineage ; Phenotype ; Mice ; Male ; Signal Transduction |
| Abstract: | Endothelial-to-mesenchymal transition (EndMT), in which endothelial cells (ECs) lose their endothelial identity and acquire mesenchymal-like features, contributes to vascular dysfunction and remodeling in atherosclerosis. However, the fate and function of these cells remain unclear. Here, we investigated their differentiation potential and functional properties to define how EndMT contributes to vascular dysfunction. Human umbilical vein ECs (HUVECs) were treated with transforming growth factor-β2 (TGF-β2) and interleukin-1β (IL-1β) for seven days to induce EndMT. Mesenchymal stem/stromal cell (MSC) identity was assessed by flow cytometry for canonical markers (CD44, CD73, CD105, CD90). Differentiation states were evaluated using published single-cell RNA sequencing (scRNA-seq) data of EndMT-treated HUVECs and validated under lineage-specific culture environments. In vivo analysis was performed using scRNA-seq data from EC lineage reporter mice in atherosclerosis models. EndMT-treated HUVECs displayed an intermediate mesenchymal phenotype, expressing CD44, CD73 and CD105 but lacking CD90, failing to meet MSC criteria. Potency analysis showed that 77 % of EndMT-treated HUVECs remained oligopotent, while 19 % acquired osteogenic and chondrogenic potential, accompanied by activation of lineage-associated transcriptional programs (RUNX2, BMPR1A, NOTCH2, WNT5A; CD151, ANXA6, DCN). In vivo, endothelial lineage-traced cells in atherosclerotic mice formed an EndMT cluster enriched for osteogenic and chondrogenic gene programs, including ossification and cartilage development pathways. We define a primed oligopotent state of EndMT-derived cells both in vitro and in vivo, marked by transition toward osteogenic and chondrogenic fates. These findings suggest that EndMT contributes to atherosclerosis by generating osteogenic- and chondrogenic-like cells, linking endothelial dysfunction to vascular calcification in disease.; (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare no competing interests. |
| Contributed Indexing: | Keywords: Atherosclerosis; Chondrogenic differentiation; Endothelial-to mesenchymal transition (EndMT); Osteogenic differentiation; Therapeutic targeting; Vascular calcification; Vascular dysfunction |
| Substance Nomenclature: | 0 (Endoglin) |
| Entry Date(s): | Date Created: 20251231 Date Completed: 20260309 Latest Revision: 20260309 |
| Update Code: | 20260309 |
| DOI: | 10.1016/j.vph.2025.107579 |
| PMID: | 41475635 |
| Database: | MEDLINE |
Journal Article