TY - JOUR

T1 - Local endothelial DNA repair deficiency causes aging-resembling endothelial-specific dysfunction

AU - Bautista-Niño, Paula K

AU - Portilla-Fernandez, Eliana

AU - Rubio-Beltrán, Eloisa

AU - van der Linden, Janette J

AU - de Vries, René

AU - van Veghel, Richard

AU - de Boer, Martine

AU - Durik, Matej

AU - Ridwan, Yanto

AU - Brandt, Renata

AU - Essers, Jeroen

AU - Menzies, Robert I

AU - Thomas, Rachel

AU - de Bruin, Alain

AU - Duncker, Dirk J

AU - van Beusekom, Heleen M M

AU - Ghanbari, Mohsen

AU - Hoeijmakers, Jan H J

AU - Sedlacek, Radislav

AU - Touyz, Rhian M

AU - Montezano, Augusto C

AU - van der Pluijm, Ingrid

AU - Danser, A H Jan

AU - Haanes, Kristian A

AU - Roks, Anton J M

N1 - © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Age Factors

KW - Aging/genetics

KW - Animals

KW - Capillary Permeability

KW - Cellular Senescence/genetics

KW - Cyclin-Dependent Kinase Inhibitor p21/genetics

KW - DNA Damage

KW - DNA Repair

KW - DNA-Binding Proteins/deficiency

KW - Endonucleases/deficiency

KW - Endothelial Cells/metabolism

KW - Endothelium, Vascular/metabolism

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Nitric Oxide/metabolism

KW - Nitric Oxide Synthase Type III/metabolism

KW - Superoxides/metabolism

KW - Vascular Stiffness

KW - Vasodilation

U2 - 10.1042/CS20190124

DO - 10.1042/CS20190124

M3 - Journal article

VL - 134

SP - 727

EP - 746

JO - Clinical Science

JF - Clinical Science

SN - 0143-5221

IS - 7

ER -