Cellular Senescence in Endothelial Dysfunction
The interior of blood vessels is lined by the endothelium. With aging, cells of the endothelium exhibit stress, inflammation, and altered behavior, contributing to the development of atherosclerosis and negatively affecting performance of the vasculature. Here, researchers discuss the degree to which this aspect of degenerative aging is caused by the presence of senescent cells. Cells become senescent constantly throughout life, but in youth are cleared efficiently by the immune system. This clearance falters later in life, allowing senescent cells to grow in number to the point of becoming disruptive to tissue structure and function. Senolytic therapies to selectively clear senescent cells have proven to be beneficial in animal studies and are presently in human trials for a number of age-related conditions.
Vascular aging is associated with the development of cardiovascular complications, in which endothelial cell senescence (ES) may play a critical role. Nitric oxide (NO) prevents human ES through inhibition of oxidative stress, and inflammatory signaling by mechanisms yet to be elucidated. Endothelial cells undergo an irreversible growth arrest and alter their functional state after a finite number of divisions, a phenomenon called replicative senescence.
We assessed the contribution of NO during replicative senescence of human aortic (HAEC) and coronary (CAEC) endothelial cells, in which accumulation of the senescence marker SA-β-Gal was quantified. We found a negative correlation in passaged cell cultures between a reduction in NO production with increased ES and the formation of reactive oxygen species and reactive nitrogen species, indicative of oxidative and nitrosative stress. The effect of ES was evidenced by reduced expression of endothelial Nitric Oxide Synthase (eNOS), Interleukin Linked Kinase (ILK), and Heat shock protein 90 (Hsp90), alongside a significant increase in the BH2/BH4 ratio, inducing the uncoupling of eNOS, favoring the production of superoxide and peroxynitrite species, and fostering an inflammatory environment, as confirmed by the levels of Cyclophilin A (CypA) and its receptor Extracellular Matrix Metalloprotease Inducer (EMMPRIN).
Thus NO prevents ES by preventing the uncoupling of eNOS, in which oxidation of BH4, which plays a key role in eNOS producing NO, may play a critical role in launching the release of free radical species, triggering an aging-related inflammatory response.