We previously identified genomic instability as a causative factor for vascular aging. In the present study, we determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 (excision repair cross-complementation group 1) DNA repair in mice (EC-knockout (EC-KO) mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared with wild-type (WT). EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared with WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide (NO) were intact. EC-KO showed increased superoxide production compared with WT, as measured in lung tissue, rich in endothelial cells (ECs). Arterial systolic blood pressure (BP) was increased at 3 months, but normal at 5 months, at which age cardiac output (CO) was decreased. Since no further signs of cardiac dysfunction were detected, this decrease might be an adaptation to prevent an increase in BP. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived NO. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung.

Centre for Cardiovascular Science The University of Edinburgh Edinburgh U K

Department of Epidemiology Erasmus University Medical Center Rotterdam The Netherlands

Department of Molecular Genetics Erasmus University Medical Center Rotterdam The Netherlands

Department of Molecular Genetics Erasmus University Medical Center Rotterdam The Netherlands CECAD Forschungszentrum Universität zu Köln Cologne Germany Princess Máxima Center for Pediatric Oncology ONCODE Institute Utrecht The Netherlands

Department of Molecular Genetics Erasmus University Medical Center Rotterdam The Netherlands Department of Radiology and Nuclear Medicine Erasmus University Medical Center Rotterdam The Netherlands

Department of Molecular Genetics Erasmus University Medical Center Rotterdam The Netherlands Department of Radiology and Nuclear Medicine Erasmus University Medical Center Rotterdam The Netherlands Department of Vascular Surgery Erasmus University Medical Center Rotterdam The Netherlands

Department of Molecular Genetics Erasmus University Medical Center Rotterdam The Netherlands Department of Vascular Surgery Erasmus University Medical Center Rotterdam The Netherlands

Division of Experimental Cardiology Department of Cardiology Thoraxcenter Erasmus University Medical Center Rotterdam The Netherlands

Division of Vascular Medicine and Pharmacology Department of Internal Medicine Erasmus University Medical Center Rotterdam The Netherlands

Division of Vascular Medicine and Pharmacology Department of Internal Medicine Erasmus University Medical Center Rotterdam The Netherlands Department of Clinical Experimental Research Glostrup Research Institute Copenhagen University Hospital Copenhagen Denmark

Division of Vascular Medicine and Pharmacology Department of Internal Medicine Erasmus University Medical Center Rotterdam The Netherlands Department of Epidemiology Erasmus University Medical Center Rotterdam The Netherlands

Division of Vascular Medicine and Pharmacology Department of Internal Medicine Erasmus University Medical Center Rotterdam The Netherlands Department of Molecular Genetics Erasmus University Medical Center Rotterdam The Netherlands

Division of Vascular Medicine and Pharmacology Department of Internal Medicine Erasmus University Medical Center Rotterdam The Netherlands Department of Pediatric and Adolescent Medicine Mayo Clinic College of Medicine Rochester MN U S A

Division of Vascular Medicine and Pharmacology Department of Internal Medicine Erasmus University Medical Center Rotterdam The Netherlands Fundacion Cardiovascular de Colombia FCV Dept of Cardiology Bucaramanga Colombia

Dutch Molecular Pathology Centre Faculty of Veterinary Medicine Department of Pathobiology Utrecht University Utrecht The Netherlands

Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow U K

Laboratory of Transgenic Models of Diseases and Czech Centre for Phenogenomics Institute of Molecular Genetics of the ASCR Prague Czech Republic

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