Aging is associated with alterations in the properties of all elements of the vascular wall including endothelium, vascular smooth muscle, and matrix. These changes result in increased vascular stiffness and isolated systolic hypertension. Both dynamic and structural changes (e.g., fracturing of elastin, increased collagen content, and accumulation of advanced glycation end products) have been described in aging. Vessel structure can additionally be regulated by alterations in matrix crosslinking. Transglutaminases (TGs) are enzymes that catalyze a transamidation reaction, leading to the crosslinking of proteins through the formation of the stable N-З-(γ- glutamyl) lysine isopeptide bonds. At least 3 of the 9 members of the TG superfamily are expressed in vascular systems. Tissue transglutaminase (TG2) in particular is ubiquitously expressed in vasculature. TG2 is confined mainly to the cytosol, and a portion of it is associated with the cell membrane and secreted out of the cell to the extracellular matrix (ECM) through an as yet unidentified mechanism where it is activated and catalyzes the transamidation reaction. Crosslinking activity of TG2 has been shown to be inhibited in vitro by NO through protein S-nitrosylation of key cysteine residue. It is well established that endothelial NO bioavailability diminishes with aging. Decreased endothelium-dependent NO synthesis in the aging vasculature leads to reduced TG2 S-nitrosylation and, thus, enhanced transamidation activity. This, in turn, results in increased crosslinking of matrix proteins and, consequently, to decreased compliance and increased stiffness of aging conduit blood vessels. Thus, NO regulates vascular stiffness characteristics by post-translational modification of a matrix modifying enzyme. TG2 remains a potential target for therapy in age-related systolic hypertension.