Ercc1 DNA repair deficiency results in vascular aging characterized by VSMC phenotype switching, ECM remodeling, and an increased stress response

• Published in: Aging cell Vol. 23; no. 5; pp. e14126 - n/a
• Main Authors: Linden, Janette, Stefens, Sanne J. M., Heredia‐Genestar, José María, Ridwan, Yanto, Brandt, Renata M. C., Vliet, Nicole, Beer, Isa, Thiel, Bibi S., Steen, Herman, Cheng, Caroline, Roks, Anton J. M., Danser, A. H. Jan, Essers, Jeroen, Pluijm, Ingrid
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.05.2024; John Wiley and Sons Inc
• Subjects: Aging; Aging - metabolism; Alcohol; Animals; Cardiovascular disease; Cardiovascular diseases; Cardiovascular system; Coronary vessels; DNA damage; DNA Repair; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Elastin; Endonucleases - deficiency; Endonucleases - genetics; Endonucleases - metabolism; Endothelium; Ercc1; ERCC1 protein; Ethanol; Extracellular matrix; Extracellular Matrix - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle contraction; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - metabolism; Phenotype; Phenotypes; Proteins; Proteoglycans; Senescence; Smooth muscle; Structure-function relationships; vascular remodeling; United States > US; aging; cardiovascular diseases; vascular remodeling; Ercc1
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.14126

Cardiovascular diseases are the number one cause of death globally. The most important determinant of cardiovascular health is a person's age. Aging results in structural changes and functional decline of the cardiovascular system. DNA damage is an important contributor to the aging process, and mice with a DNA repair defect caused by Ercc1 deficiency display hypertension, vascular stiffening, and loss of vasomotor control. To determine the underlying cause, we compared important hallmarks of vascular aging in aortas of both Ercc1Δ/− and age‐matched wildtype mice. Additionally, we investigated vascular aging in 104 week old wildtype mice. Ercc1Δ/− aortas displayed arterial thickening, a loss of cells, and a discontinuous endothelial layer. Aortas of 24 week old Ercc1Δ/− mice showed phenotypical switching of vascular smooth muscle cells (VSMCs), characterized by a decrease in contractile markers and a decrease in synthetic markers at the RNA level. As well as an increase in osteogenic markers, microcalcification, and an increase in markers for damage induced stress response. This suggests that Ercc1Δ/− VSMCs undergo a stress‐induced contractile‐to‐osteogenic phenotype switch. Ercc1Δ/− aortas showed increased MMP activity, elastin fragmentation, and proteoglycan deposition, characteristic of vascular aging and indicative of age‐related extracellular matrix remodeling. The 104 week old WT mice showed loss of cells, VSMC dedifferentiation, and senescence. In conclusion, Ercc1Δ/− aortas rapidly display many characteristics of vascular aging, and thus the Ercc1Δ/− mouse is an excellent model to evaluate drugs that prevent vascular aging in a short time span at the functional, histological, and cellular level. Ercc1Δ/− mice are defective in DNA repair, resulting in age‐related diseases including cardiovascular aging. To determine the underlying cause, we investigated important hallmarks of vascular aging in aortas of both Ercc1Δ/− and age‐matched wildtype mice. A comparative analysis revealed arterial thickening, cell loss, and disrupted endothelial layers in Ercc1Δ/− compared to wildtype aortas. Additionally, 24‐week‐old Ercc1Δ/− mice displayed VSMC phenotypic switching, marked by altered gene expression and a stress‐induced contractile‐to‐osteogenic phenotype switch. Ercc1Δ/− aortas exhibited increased MMP activity, elastin fragmentation, and proteoglycan deposition, indicating age‐related extracellular matrix remodeling. Importantly, the Ercc1Δ/− aortas showed more overlap with human vascular aging than aged 104 week old wildtype aortas. In summary, Ercc1Δ/− mice rapidly exhibit key vascular aging characteristics, making them an ideal model to evaluate anti‐aging drugs at a functional, histological and cellular level.