DNA Damage-related Vascular Dysfunction: Pathways and Interventions
DNA schade-gerelateerde vasculaire disfunctie mechanismen en interventies
In my thesis the role of DNA damage on vascular function was studied. DNA damage is one of the primary causes of aging, which is the strongest independent risk factor for chronic diseases such as cancer and cardiovascular diseases. Mice with defective DNA repair are excellent exploration tools because they rapidly reproduce hallmarks of human aging. Most of the studies included in my thesis were performed in mouse models with defects in DNA damage repair, either in all body organs or restricted to vascular endothelium or smooth muscle.
In mice with whole-body defective DNA damage repair I found that phosphodiesterase 1 (PDE1) is increased and this causes impaired nitric oxide signaling; PDE1 is also increased in human senescent vascular smooth muscle cells, and by means of candidate gene look-up analyses, I found that genetic variants in the PDE1A gene were associated with increased diastolic blood pressure and carotid intima media thickness, two hallmarks of human age-related vascular dysfunction. Assessment of cardiovascular function in mice with DNA damage only in the vascular endothelium or smooth muscle revealed that both DNA damage in endothelial cells and in vascular smooth muscle, in what seems to be a cell-autonomous way, lead to specific changes in the vasodilatory pathways that are relevant for aging-related vascular disease. Moreover, interventions such as dietary restriction and phosphodiesterase inhibition improve vascular function in our mouse models of accelerated aging. Overall, my thesis findings bring us one step closer to uncover the mechanisms underlying the association of age and cardiovascular diseases.
|Vascular aging, DNA damage, cardiovascular disease, aging|
|A.H.J. Danser (Jan) , O.H. Franco (Oscar) , A.J.M. Roks (Anton) , M. Ghanbari (Mohsen)|
|Erasmus University Rotterdam|
|The author received a grant to pursue her doctoral studies at the Erasmus MC from the Administrative Department of Science, Technology and Innovation of Colombia—Colciencias (Call 617 of 2013).|
|Organisation||Department of Pharmacology|
Bautista-Niño, P.K. (2017, December 20). DNA Damage-related Vascular Dysfunction: Pathways and Interventions. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/103487