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

Singh, Pratibha LU ; Sun, Jiangming LU orcid ; Cavalera, Michele LU ; Al-Sharify, Dania LU orcid ; Matthes, Frank LU orcid ; Barghouth, Mohammad LU ; Tengryd, Christoffer LU ; Dunér, Pontus LU ; Persson, Ana LU and Sundius, Lena LU , et al. (2024) In Nature Communications 15. p.1-18
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
15
article number
10464
pages
1 - 18
publisher
Nature Publishing Group
external identifiers
  • pmid:39653743
  • scopus:85211816682
ISSN
2041-1723
DOI
10.1038/s41467-024-50753-8
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2024.
id
4fe4265c-c95c-4a3c-addf-a662f761bdc8
date added to LUP
2025-01-10 14:40:13
date last changed
2025-07-12 05:58:21
@article{4fe4265c-c95c-4a3c-addf-a662f761bdc8,
  abstract     = {{<p>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.</p>}},
  author       = {{Singh, Pratibha and Sun, Jiangming and Cavalera, Michele and Al-Sharify, Dania and Matthes, Frank and Barghouth, Mohammad and Tengryd, Christoffer and Dunér, Pontus and Persson, Ana and Sundius, Lena and Nitulescu, Mihaela and Bengtsson, Eva and Rattik, Sara and Engelbertsen, Daniel and Orho-Melander, Marju and Nilsson, Jan and Monaco, Claudia and Goncalves, Isabel and Edsfeldt, Andreas}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  pages        = {{1--18}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Dysregulation of MMP2-dependent TGF-ß2 activation impairs fibrous cap formation in type 2 diabetes-associated atherosclerosis}},
  url          = {{http://dx.doi.org/10.1038/s41467-024-50753-8}},
  doi          = {{10.1038/s41467-024-50753-8}},
  volume       = {{15}},
  year         = {{2024}},
}