Old Friends, New Faces in Endothelial Dysfunction and Senescence

Significance: Onset and progression of cardiovascular diseases are tightly linked to the aging process. Aging results in structural and functional changes including endothelial dysfunction and senescence, thereby impairing vascular functions. The molecules involved in these processes are far from understood. Recent Advances: The cellular redox homeostasis and proteostasis as well as mitochondrial functionality play key roles in the maintenance of the endothelium and are impaired in senescence and aging. Over the last few years, several proteins, which were previously ascribed functions in other pathways and/or cellular compartments, have been shown to be involved in the regulation of these processes. These include G protein-coupled receptors, chaperones in the endoplasmic reticulum, and the proteins cyclin-dependent kinase inhibitor 1B/p27 KIP1 and telomerase reverse transcriptase, which were assigned previously unknown functions in the mitochondria. Based on the specific functions of these proteins, modulation of their signaling pathways, activity or subcellular localization, might provide leads for new therapeutic approaches targeting aging-associated endothelial dysfunction and vascular diseases. Critical Issues: The proteins described in this review undoubtedly have functions in endothelial cells and the vasculature. However, before they are considered as potential therapeutic targets, potential side effects in other cell types and tissues should be critically investigated. This might be most important for proteins, which have diverging functions in different compartments of a cell. Future Directions: Although several new pathways affecting endothelial functionality have been identified and might be of therapeutic relevance, further research is required to fully understand the exact molecular mechanisms. Antioxid. Redox Signal. 00, 000–000.