Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

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

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Pre-clinical effects of highly potent MEK1/2 inhibitors on rat cerebral vasculature after organ culture and subarachnoid haemorrhage

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. G16R single nucleotide polymorphism but not haplotypes of the β(2)-adrenergic receptor gene alters cardiac output in humans

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Central and cerebrovascular effects of leg crossing in humans with sympathetic failure

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Effects of blood pressure lowering and metabolic control on systolic left ventricular function in Type II diabetes mellitus

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Estrogen receptors α, β and GPER in the CNS and trigeminal system - molecular and functional aspects

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Lasmiditan inhibits calcitonin gene-related peptide release in the rodent trigeminovascular system

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Paula K Bautista-Niño
  • Eliana Portilla-Fernandez
  • Eloisa Rubio-Beltrán
  • Janette J van der Linden
  • René de Vries
  • Richard van Veghel
  • Martine de Boer
  • Matej Durik
  • Yanto Ridwan
  • Renata Brandt
  • Jeroen Essers
  • Robert I Menzies
  • Rachel Thomas
  • Alain de Bruin
  • Dirk J Duncker
  • Heleen M M van Beusekom
  • Mohsen Ghanbari
  • Jan H J Hoeijmakers
  • Radislav Sedlacek
  • Rhian M Touyz
  • Augusto C Montezano
  • Ingrid van der Pluijm
  • A H Jan Danser
  • Kristian A Haanes
  • Anton J M Roks
View graph of relations

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.

Original languageEnglish
JournalClinical science (London, England : 1979)
Volume134
Issue number7
Pages (from-to)727-746
Number of pages20
ISSN0143-5221
DOIs
Publication statusPublished - 2020

    Research areas

  • Age Factors, Aging/genetics, Animals, Capillary Permeability, Cellular Senescence/genetics, Cyclin-Dependent Kinase Inhibitor p21/genetics, DNA Damage, DNA Repair, DNA-Binding Proteins/deficiency, Endonucleases/deficiency, Endothelial Cells/metabolism, Endothelium, Vascular/metabolism, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide/metabolism, Nitric Oxide Synthase Type III/metabolism, Superoxides/metabolism, Vascular Stiffness, Vasodilation

ID: 60887706