Endothelial-Ercc1 DNA repair deficiency provokes blood-brain barrier dysfunction.

Cathrin E Hansen, Davide Vacondio, Lennart van der Molen, Annika A Jüttner, Wing Ka Fung, Manon Karsten, Bert van Het Hof, Ruud D Fontijn, Gijs Kooij, Maarten E Witte, Anton J M Roks, Helga E de Vries, Inge Mulder, Nienke M de Wit

Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. [email protected] UMC location Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. [email protected]. · pubmed

Paper

Abstract

Aging of the brain vasculature plays a key role in the development of neurovascular and neurodegenerative diseases, thereby contributing to cognitive impairment. Among other factors, DNA damage strongly promotes cellular aging, however, the role of genomic instability in brain endothelial cells (EC) and its potential effect on brain homeostasis is still largely unclear. We here investigated how endothelial aging impacts blood-brain barrier (BBB) function by using excision repair cross complementation group 1 (ERCC1)-deficient human brain ECs and an EC-specific Ercc1 knock out (EC-KO) mouse model. In vitro, ERCC1-deficient brain ECs displayed increased senescence-associated secretory phenotype expression, reduced BBB integrity, and higher sprouting capacities due to an underlying dysregulation of the Dll4-Notch pathway. In line, EC-KO mice showed more P21

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Research summary

The paper investigates the role of DNA repair deficiency in brain endothelial cells and its impact on blood-brain barrier dysfunction, which is a significant aspect of aging and neurodegenerative diseases. By focusing on the underlying mechanisms of endothelial aging and its effects on brain homeostasis, it addresses a root cause of age-related decline in cognitive function. However, while the findings are solid and contribute to understanding the aging process, they do not present a major breakthrough or transformative implications for longevity research, thus warranting a moderate impact score.

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