Metabolic syndrome-associated murine aortic wall stiffening is associated with premature elastic fibers aging.

Type 2 diabetes (T2D) constitutes a major public health problem, and despite prevention efforts, this pandemic disease is one of the deadliest diseases in the world. In 2022, 6.7 million patients with T2D died prematurely from vascular complications. Indeed, diabetes increases the risk of myocardial infarction or stroke eightfold. The identification of the molecular factors involved in the occurrence of cardiovascular complications and their prevention are therefore major axes. Our hypothesis is that factors brought into play during physiological aging appear prematurely with diabetes progression. Our study focused on the aging of the extracellular matrix (ECM), a major element in the maintenance of vascular homeostasis. We characterized the morphological and functional aspects of aorta, with a focus on the collagen and elastic fibers of diabetic mice aged from 6 mo to nondiabetic mice aged 6 mo and 20 mo. The comparison with the two nondiabetic models (young and old) highlighted an exacerbated activity of proteases, which could explain a disturbance in the collagen accumulation and an excessive degradation of elastic fibers. Moreover, the generation of circulating elastin-derived peptides reflects premature aging of the ECM. These extracellular elements contribute to the appearance of vascular rigidity, often the origin of pathologies such as hypertension and atherosclerosis. In conclusion, we show that diabetic mice aged 6 mo present the same characteristics of ECM wear as those observed in mice aged 20 mo. This accelerated aortic wall remodeling could then explain the early onset of cardiovascular diseases and, therefore, the premature death of patients with T2D.NEW & NOTEWORTHY Aortic elastic fibers of young (6-mo old) individuals with diabetes degrade prematurely and exhibit an appearance like that found in aged (20-mo old) nondiabetic mice. Exacerbated elastolysis and elastin-derived peptide production are characteristic elements, contributing to early aortic wall rigidity and hypertension development. Therefore, limiting this early aging could be a judicious therapeutic approach to reduce cardiovascular complications and premature death in patients with diabetes.

Elastin haploinsufficiency impedes the progression of arterial calcification in MGP-deficient mice.

Matrix gla protein (MGP) is a potent inhibitor of extracellular matrix (ECM) mineralization. MGP-deficiency in humans leads to Keutel syndrome, a rare genetic disease hallmarked by abnormal soft tissue calcification. MGP-deficient (Mgp(-/-)) mice show progressive deposition of hydroxyapatite minerals in the arterial walls and die within 2 months of age. The mechanism of antimineralization function of MGP is not fully understood. We examined the progression of vascular calcification and expression of several chondrogenic/osteogenic markers in the thoracic aortas of Mgp(-/-) mice at various ages. Although cells with chondrocyte-like morphology have been reported in the calcified aorta, our gene expression data indicate that chondrogenic/osteogenic markers are not upregulated in the arteries prior to the initiation of calcification. Interestingly, arterial calcification in Mgp(-/-) mice appears first in the elastic laminae. Considering the known mineral scaffolding function of elastin (ELN), a major elastic lamina protein, we hypothesize that elastin content in the laminae is a critical determinant for arterial calcification in Mgp(-/-) mice. To investigate this, we performed micro-computed tomography (µCT) and histological analyses of the aortas of Mgp(-/-);Eln(+/-) mice and show that elastin haploinsufficiency significantly reduces arterial calcification in this strain. Our data suggest that MGP deficiency leads to alterations of vascular ECM that may in turn initiate arterial calcification.