TY - JOUR
T1 - Dysregulation of MMP2-dependent TGF-ß2 activation impairs fibrous cap formation in type 2 diabetes-associated atherosclerosis
AU - Singh, Pratibha
AU - Sun, Jiangming
AU - Cavalera, Michele
AU - Al-Sharify, Dania
AU - Matthes, Frank
AU - Barghouth, Mohammad
AU - Tengryd, Christoffer
AU - Dunér, Pontus
AU - Persson, Ana
AU - Sundius, Lena
AU - Nitulescu, Mihaela
AU - Bengtsson, Eva
AU - Rattik, Sara
AU - Engelbertsen, Daniel
AU - Orho-Melander, Marju
AU - Nilsson, Jan
AU - Monaco, Claudia
AU - Goncalves, Isabel
AU - Edsfeldt, Andreas
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-024-50753-8
DO - 10.1038/s41467-024-50753-8
M3 - Article
C2 - 39653743
AN - SCOPUS:85211816682
SN - 2041-1723
VL - 15
SP - 1
EP - 18
JO - Nature Communications
JF - Nature Communications
M1 - 10464
ER -