Identification of Molecular Features Associated with Vascular Alterations in Aging

ABSTRACT Aging is a complex biological process that significantly impacts tissue and organ physiology, particularly the vascular system. This decline in vascular function is a major risk factor for various chronic diseases, including cardiovascular diseases, stroke, neurodegenerative disorders, obesity, sarcopenia, osteoarthritis, and cancer. Endothelial cell senescence, characterized by loss of function and increased secretion of harmful factors, contributes to vascular dysfunction. These changes are driven by processes such as inflammation, oxidative stress, and alterations in signaling pathways, leading to molecular changes and the accumulation of senescent endothelial cells. Detecting these changes involves assessing differential expression and localization of extracellular proteins in vascular endothelial cells (VECs), which are crucial in age-related vascular dysfunctions. To enhance our understanding of these molecular mechanisms and age-related pathologies, innovative techniques for imaging molecular and cellular alterations are needed. In vivo phage display has translational potential for identifying aging markers and VEC targeting ligands. Our team has successfully identified peptide ligands for various biological processes, including cancer, obesity, atherosclerosis, trauma, and retinopathy. In this proposal, we aim to isolate and characterize peptide ligands targeting VECs in young versus aged mice in vivo and senescent versus non-senescent murine VECs in vitro. Our preliminary data from aged mice tissues reveal thousands of shared and tissue-specific peptide ligands. Aim 1 involves additional biopanning in young mice for comparison with aged animal peptides. Aim 2 focuses on identifying peptide ligands specific to senescent VEC receptors through further biopanning. Aim 3 aims to validate the specificity of promising peptide ligands in cells and tissues, identifying their receptors and evaluating their expression in aged tissues. Completing these aims will provide an innovative approach to study vascular aging, potentially paving the way for senolytic drug development or targeting strategies for age-related vascular dysfunction-related diseases.