Elevated PDGF-BB from Bone Impairs Hippocampal Vasculature by Inducing PDGFRβ Shedding from Pericytes

Guanqiao Liu, Jiekang Wang, Zhiliang Wei, Ching Lien Fang, Ke Shen, Cheng Qian, Cheng Qi, Tong Li, Peisong Gao, Philip C. Wong, Hanzhang Lu, Xu Cao, Mei Wan

Research output: Contribution to journalArticlepeer-review

Abstract

Evidence suggests a unique association between bone aging and neurodegenerative/cerebrovascular disorders. However, the mechanisms underlying bone-brain interplay remain elusive. Here platelet-derived growth factor-BB (PDGF-BB) produced by preosteoclasts in bone is reported to promote age-associated hippocampal vascular impairment. Aberrantly elevated circulating PDGF-BB in aged mice and high-fat diet (HFD)-challenged mice correlates with capillary reduction, pericyte loss, and increased blood-brain barrier (BBB) permeability in their hippocampus. Preosteoclast-specific Pdgfb transgenic mice with markedly high plasma PDGF-BB concentration faithfully recapitulate the age-associated hippocampal BBB impairment and cognitive decline. Conversely, preosteoclast-specific Pdgfb knockout mice have attenuated hippocampal BBB impairment in aged mice or HFD-challenged mice. Persistent exposure of brain pericytes to high concentrations of PDGF-BB upregulates matrix metalloproteinase 14 (MMP14), which promotes ectodomain shedding of PDGF receptor β (PDGFRβ) from pericyte surface. MMP inhibitor treatment alleviates hippocampal pericyte loss and capillary reduction in the conditional Pdgfb transgenic mice and antagonizes BBB leakage in aged mice. The findings establish the role of bone-derived PDGF-BB in mediating hippocampal BBB disruption and identify the ligand-induced PDGFRβ shedding as a feedback mechanism for age-associated PDGFRβ downregulation and the consequent pericyte loss.

Original languageEnglish (US)
Article number2206938
JournalAdvanced Science
Volume10
Issue number20
DOIs
StatePublished - Jul 18 2023

Keywords

  • PDGFRβ
  • blood-brain barrier permeability
  • bone
  • circulating platelet-derived growth factor-BB
  • receptor shedding

ASJC Scopus subject areas

  • General Engineering
  • General Chemical Engineering
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • General Materials Science
  • General Physics and Astronomy
  • Medicine (miscellaneous)

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