Dysregulation of MMP2-dependent TGF-ß2 activation impairs fibrous cap formation in type 2 diabetes-associated atherosclerosis

Pratibha Singh, Jiangming Sun, Michele Cavalera, Dania Al-Sharify, Frank Matthes, Mohammad Barghouth, Christoffer Tengryd, Pontus Dunér, Ana Persson, Lena Sundius, Mihaela Nitulescu, Eva Bengtsson, Sara Rattik, Daniel Engelbertsen, Marju Orho-Melander, Jan Nilsson, Claudia Monaco, Isabel Goncalves and Andreas Edsfeldt ()
Additional contact information
Pratibha Singh: Lund University
Jiangming Sun: Lund University
Michele Cavalera: Lund University
Dania Al-Sharify: Lund University
Frank Matthes: Lund University
Mohammad Barghouth: Lund University
Christoffer Tengryd: Lund University
Pontus Dunér: Lund University
Ana Persson: Lund University
Lena Sundius: Lund University
Mihaela Nitulescu: Lund University
Eva Bengtsson: Lund University
Sara Rattik: Lund University
Daniel Engelbertsen: Lund University
Marju Orho-Melander: Lund University
Jan Nilsson: Lund University
Claudia Monaco: University of Oxford
Isabel Goncalves: Lund University
Andreas Edsfeldt: Lund University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Type 2 diabetes is associated with cardiovascular disease, possibly due to impaired vascular fibrous repair. Yet, the mechanisms are elusive. Here, we investigate alterations in the fibrous repair processes in type 2 diabetes atherosclerotic plaque extracellular matrix by combining multi-omics from the human Carotid Plaque Imaging Project cohort and functional studies. Plaques from type 2 diabetes patients have less collagen. Interestingly, lower levels of transforming growth factor-ß distinguish type 2 diabetes plaques and, in these patients, lower levels of fibrous repair markers are associated with cardiovascular events. Transforming growth factor-ß2 originates mostly from contractile vascular smooth muscle cells that interact with synthetic vascular smooth muscle cells in the cap, leading to collagen formation and vascular smooth muscle cell differentiation. This is regulated by free transforming growth factor-ß2 which is affected by hyperglycemia. Our findings underscore the importance of transforming growth factor-ß2-driven fibrous repair in type 2 diabetes as an area for future therapeutic strategies.

Date: 2024
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DOI: 10.1038/s41467-024-50753-8

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