The most common trigger of sepsis and septic shock is bacterial lipopolysaccharide (LPS). Endothelial cells are among the first to encounter LPS directly. Generally, their function is closely linked to active endothelial NO Synthase (eNOS), which is significantly reduced under septic conditions. LPS treatment of endothelial cells leads to their activation and apoptosis, resulting in loss of integrity and vascular leakage, a hallmark of septic shock. Hence, therapies that prevent endothelial leakage or restore the endothelial barrier would be invaluable for patients. Adhesion GPCRs (aGPCRs) have been largely overlooked in this context, although particularly one of them, ADGRL2/LPHN2, has been implicated in endothelial barrier function. Our study shows that overexpression of ADGRL2 protects endothelial cells from LPS-induced activation, apoptosis, and impaired migration. Mechanistically, ADGRL2 preserves eNOS activity by shifting its binding from Caveolin-1 to Heat Shock Protein 90. Furthermore, ADGRL2 enhances antioxidative responses by increasing NRF2 activity. Notably, we found that this function may be evolutionarily conserved. In the absence of lat-2, a homolog of ADGRL2 in Caenorhabditis elegans, worms show higher ROS levels and altered stress response gene expression. Additionally, lat-2 mutants have a significantly reduced lifespan, altogether indicating a protective role of ADGRL2 against oxidative stress across species.

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.