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

• DOI: 10.1111/acel.14126
• Publication Date: 2024-03-07T13:14:18Z
• Authors: Janette van der L...; Sanne J. M. Stefens; José María Heredi...; Yanto Ridwan; Renata M. C. Brandt; Nicole van Vliet; Isa de Beer; Bibi S. van Thiel; Herman Steen; Caroline Cheng; Anton J. M. Roks; A. H. Jan Danser; Jeroen Essers; Ingrid van der Pl...
• Keywords: Mice, Knockout; Aging; 0303 health sciences; DNA Repair; Myocytes, Smooth Muscle; Endonucleases; Muscle, Smooth, Vascular; Extracellular Matrix; DNA-Binding Proteins; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Phenotype; SDG 3 - Good Health and Well-being; Animals; Research Articles

AbstractCardiovascular 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.