ArticleNature communications2026
Endothelial cell-microglia crosstalk mediates heart failure-associated synaptic loss and cognitive impairment in male mice.
Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Cognitive impairment affects 30%-80% of patients with heart failure, yet the mechanisms beyond reduced brain blood flow remain poorly defined. Here we show that circulating factors released during heart failure trigger senescence of brain blood-vessel endothelial cells, which in turn drives synaptic loss and cognitive decline through crosstalk between endothelial cells and microglia, the brain's immune cells. Using a pressure-overload model (transverse aortic constriction) combined with plasma transfer in 8-month-old male mice, we found that elevated circulating TGFβ2 acts on endothelial TGFBR2 and induces the secreted protein SPARC via a non-canonical MEK/ERK-MYC pathway. Endothelial SPARC then activates microglial TLR4, promoting neuroinflammation and abnormal engulfment of synapses. Endothelial deletion of Tgfbr2 or Sparc, and microglial deletion of Tlr4, each preserved synapses and improved cognition, and pharmacological Tlr4 inhibition was protective. These findings define an endothelial-microglia signaling axis and a potential therapeutic target in heart failure-associated cognitive impairment.
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