Endothelial epigenetic senescence driven microglial activation mediates cardio-retinal neuroinflammation in heart failure.

RATIONALE: Heart failure (HF) is increasingly recognized as a systemic disorder that extends beyond the heart and affects neurovascular tissues, including the retina. However, the mechanisms by which circulating factors from HF trigger retinal neuroinflammation remain unclear. METHODS: HF was induced in adult mice by transverse aortic constriction (TAC). Retinal structure and function were evaluated using optical coherence tomography (OCT) and electroretinography (ERG). Parabiosis and plasma transfer experiments were performed to assess the role of circulating factors. Endothelial senescence, microglial activation, and inflammatory signaling were analyzed using immunofluorescence, qPCR, and molecular assays. The functional relevance of TGFβ2 and microglia was tested using anti-TGFβ2 antibody administration and microglial depletion with PLX5622 treatment. RESULTS: TAC mice exhibited pronounced retinal thinning, diminished electroretinography (ERG) amplitudes, and reduced vascular density. Exposure of healthy mice to HF plasma reproduced these abnormalities, indicating that circulating mediators drive retinal injuries. TGFβ2 levels were markedly elevated in the plasma of both patients with HF and TAC mice. Mechanistically, TGFβ2 activated the pSMAD2/EP300 pathway in retinal endothelial cells, promoting H3K9 acetylation, P21 induction, and endothelial cell senescence. Senescent endothelial cells release proinflammatory factors that activate retinal microglia, leading to hypertrophic morphology, enhanced synaptic phagocytosis, and upregulation of cytokines such as IL1β, TNFα, and IL6. Neutralization of TGFβ2 or microglial depletion markedly reduced inflammation, preserved the retinal architecture, and restored visual function. CONCLUSIONS: Elevated TGFβ2 levels in heart failure drive retinal endothelial epigenetic senescence, which secondarily activates microglia and induces neuroinflammation. Endothelial-specific disruption of TGFβ2 signaling is sufficient to protect the retina independently of primary cardiac recovery. Targeting the TGFβ2-endothelial-microglia axis may represent a promising therapeutic strategy for preventing retinal neurovascular degeneration associated with systemic cardiac disease.