Posttranslational Modification Cross‐Talk in Vascular Cells: Molecular Mechanisms and Therapeutic Implications for Atherosclerosis

ABSTRACT

Atherosclerosis is driven by coordinated changes in endothelial cells (ECs), macrophages, and vascular smooth muscle cells (VSMCs). Post‐translational modifications (PTMs), phosphorylation, acetylation, ubiquitination, SUMOylation, O‐GlcNAcylation, palmitoylation, ISGylation, and ADP‐ribosylation, integrate metabolic, inflammatory, and mechanical inputs at a limited number of signaling nodes. This review argues that these modifications interact according to four definable relationships rather than merely co‐occurring. In competitive cross‐talk, two marks contest one acceptor residue, as when O‐GlcNAcylation displaces phosphorylation at the Akt site of endothelial nitric oxide synthase. In hierarchical cross‐talk, one modification licenses another, as when Ser536 phosphorylation of NF‐κB p65 recruits p300 and permits Lys310 acetylation. In enzyme‐directed cross‐talk, a modification acts on the writer or eraser of a different system, as HDAC9 does on IκB kinases. In cofactor‐coupled cross‐talk, sirtuin‐dependent deacylation and PARP1‐dependent ADP‐ribosylation draw on one limiting NAD ⁺ pool. We rank nodes against four stated criteria, grade every finding on a five‐level evidence scheme, and apply the framework to phosphorylation–O‐GlcNAcylation, ubiquitination–SUMOylation, and acetylation–ubiquitination interactions across the three vascular cell types. Of the cross‐talk relationships invoked, five are supported at residue resolution by a substitution experiment, and two of these were obtained in vascular cells; the remainder are inferred from enzyme‐level regulation or from pathway convergence. Candidate intervention points include HDAC9, SENP3, OGT, UBA1, and the NAD ⁺ pool, none of which has been evaluated in a cardiovascular outcome trial.