Background <p>Cardiovascular diseases are the leading cause of mortality worldwide, with aging and endothelial dysfunction being key contributors to its progression. Age-related vascular dysfunction is characterized by impaired endothelial-dependent relaxation, increased vascular inflammation, and heightened susceptibility to injury, all of which exacerbate cardiovascular risk. The multi-functional protein Niban restores vascular function following injury, with reduced Niban phosphorylation linked to activation of mitogen-activated protein kinase (MAPK) pathways. We hypothesized that reduced Niban phosphorylation and increased inflammatory MAPK signaling would be associated with vascular dysfunction in aging that can be attenuated by NiPp, a cell permeant phosphomimetic peptide of Niban.</p> Methods and results <p>Aortas from young (3-months-old, <i>N</i> = 8) and aged (20- to 23-month-old <i>N</i> = 8) rats were assessed for vascular reactivity as well as protein levels and protein phosphorylation. Aged aortas displayed impaired contractility, endothelial-dependent relaxation, reduced phosphorylated Niban levels, and increased phosphorylation of inflammatory MAPK pathway elements including c-Jun N-terminal kinase, MAP kinase-activated protein kinase 2, phosphorylated cAMP response element-binding protein, and downstream vascular cell adhesion molecule-1. Aged aortas also exhibited greater IL-1β-induced loss of endothelial-dependent relaxation ex vivo, which was attenuated by NiPp treatment.</p> Conclusion <p>These results identify reduced Niban phosphorylation and increased MAPK signaling as contributors to age-related endothelial dysfunction and highlight Niban phosphorylation as a possible target for treating vascular aging and associated cardiovascular diseases.</p>