dissertationThe role of telomere dysfunction, defined as telomere shortening that leads to telomere uncapping, in arterial aging and hypertension is currently unexplored. Understanding the role that telomere dysfunction plays in arterial aging could lead to novel therapies and interventions designed to blunt, stop, or even reverse the arterial dysfunction that precedes cardiovascular diseases. Likewise, understanding the role that arterial telomere dysfunction plays in the pathogenesis of hypertension could ultimately produce therapies and interventions that treat or reverse high arterial blood pressure. To gain insight into the role of telomere dysfunction in arterial aging and hypertension, we first determined the association between telomere dysfunction, cellular senescence, and inflammation in aging and hypertension in human arteries. Next, we determined if arterial telomere uncapping, independent of telomere shortening, leads to cellular senescence and ensuing inflammation and oxidative stress, and subsequent arterial endothelial dysfunction, increased arterial blood pressure, and pulse wave velocity in a mouse model of telomere uncapping. Our findings demonstrate that arterial telomere uncapping occurs with advancing age and is associated with hypertension independent of telomere length. Furthermore, our results reveal that telomere uncapping leads to arterial dysfunction that is comparable iv to that seen in arterial aging and hypertension. We believe these studies lay the clinical and mechanistic foundation for future studies aimed at establishing the prognostic value of telomere uncapping as a biomarker for CVDs
