Telomere uncapping as a novel mechanism for endothelial cell senescence and age-related arterial dysfunction

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SUMMARY/ABSTRACT Cardiovascular diseases (CVDs) are the leading cause of death in elderly individuals. During advancing age, large arteries become stiffer and endothelium-dependent dilation (EDD) is impaired, both of which predict future CVD. Chronic inflammation and oxidative stress are elevated with aging and drive arterial stiffening and suppress EDD. Senescent cells accumulate in advanced age and promote inflammation and oxidative stress, however, the mechanisms that lead to cellular senescence in vivo remain elusive. The working hypothesis of this proposal is that aging results in endothelial cell telomere uncapping that induces senescence and suppresses arterial function in advancing age. To explore this, I will determine if aging results in telomere uncapping that is associated with senescence in endothelial cells. To determine the extent to which telomere uncapping contributes to senescence, I will induce cell death in senescent, but not non-senescent cells using senolytics and evaluate telomere uncapping and senescence. Furthermore, I will induce telomere uncapping in mice by deleting the key telomere capping protein TRF2 specifically from endothelial cells. In these mice, I will examine arterial stiffness, EDD, and hallmarks of physiological and cellular aging. The proposed studies represent a novel application of telomere biology that will enhance our understanding of how cells become senescent, as well as the physiological consequences of endothelial cell senescence. The findings of these studies are clinically relevant as senolytics are currently being evaluated in clinical trials in humans.