Endothelial cell-microglia crosstalk mediates heart failure-associated synaptic loss and cognitive impairment in male mice

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. Cardiac failure is associated with cognitive impairment. Here, the authors show that blood-borne signals can induce brain endothelial cell-release of SPARC, resulting in the activation of microglia, synapse loss, and cognitive decline following transverse aortic constriction in mice.