Vasculopathy-Driven Fibrosis in Systemic Sclerosis: Insights from Apelin/APJ, MFG-E8, Extracellular ATP/P2Y2, and Oxidative Stress Signaling

Systemic sclerosis (SSc) involves vasculopathy, immune dysregulation, and fibrosis, but the causal links between vascular injury and persistent fibroblast activation remain incompletely resolved. This focused narrative review examines apelin/APJ, milk fat globule–EGF factor 8 (MFG-E8), extracellular ATP/P2Y2, and kaempferol-associated redox modulation. Human SSc observations associate reduced apelin and MFG-E8 with disease features. Separate experiments in cultured fibroblasts and SSc-related mouse models support inhibition of TGF-β/Smad responses by apelin/APJ, restraint of latent TGF-β activation by MFG-E8, and ATP/P2Y2-dependent inflammatory and collagen responses. Kaempferol reduces oxidative injury and fibrosis-related outcomes in experimental systems; its dependence on AhR–Nrf2 signaling in SSc has not been established. APJ agonist studies in non-SSc pulmonary arterial hypertension models provide additional pharmacological context but do not establish efficacy in SSc. We propose a testable loss-and-gain model in which diminished protective signals and increased injury-associated signaling may jointly favor fibrosis. Direct interactions among all four pathways, their temporal ordering, and the causal contribution of vasculopathy to their combined alteration remain unproven. The review distinguishes human observations, SSc-related experiments, evidence from other conditions, and hypotheses, and identifies experiments needed to test the integrated model.