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August 16, 2026Nature CommunicationsOpen Access

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

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Authors

MWMengdan WangXYXiaoxuan YuTATursunjan Aziz

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Overview

Preclinical study reveals that endothelial-microglial SPARC-TLR4 signaling drives cognitive decline in heart failure mice, indicating a potential target for therapeutic intervention.

Key Points

  • To identify the molecular mechanisms connecting heart failure to brain endothelial cell senescence, synaptic loss, and cognitive impairment.
  • Utilized a transverse aortic constriction pressure-overload model combined with plasma transfer in 8-month-old male mice.
  • Assessed cell-specific genetic knockouts of endothelial Tgfbr2 and Sparc, microglial Tlr4 deletion, and pharmacological TLR4 inhibition.
  • Circulating TGFβ2 activated endothelial TGFBR2, promoting the secretion of SPARC through a non-canonical MEK/ERK–MYC pathway.
  • Endothelial SPARC engaged microglial TLR4, triggering neuroinflammation and aberrant microglial engulfment of synapses.
  • Genetic ablation of endothelial Tgfbr2 or Sparc, microglial Tlr4 knockout, and pharmacological TLR4 inhibition each protected synapses and improved cognitive function.

Cite This Study

Wang et al. (2026) studied this question.

synapsesocial.com/papers/6a81796af2fb91fc834ac7ffhttps://doi.org/10.1038/s41467-026-76687-x
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Microglial metabolic reprogramming drives cognitive decline in heart failure with preserved ejection fraction2025
  2. 2Epigenetic gene-expression links heart failure to memory impairment2020 · 2 citations
  3. 3Angiotensin II–Mediated Neuroinflammation in the Hippocampus Contributes to Neuronal Deficits and Cognitive Impairment in Heart Failure Rats2023 · 36 citations
  4. 4Abstract DP317: Endothelial C3aR regulates cerebrovascular transmigration of myeloid cells in VCID2026
  5. 5EXPRESS: Downregulation of <i>Trpv4</i> and <i>Klf2</i> in brain microvessels is associated with the progression of neurovascular dysfunction and cognitive impairment in a model of heart failure with preserved ejection fraction.2026