Elevated PDGF-BB from Bone Impairs Hippocampal Vasculature by Inducing PDGFRβ Shedding from Pericytes.
Elevated PDGF-BB from Bone Impairs Hippocampal Vasculature by Inducing PDGFRβ Shedding from Pericytes.
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DOI：
10.1002/advs.202206938
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发表时间：
2023-07
期刊：
影响因子：
--
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文献类型：
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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. The study establishes the role of platelet‐derived growth factor‐BB (PDGF‐BB) as a new member of the bone‐derived pro‐aging factor family. Once PDGF‐BB reaches levels beyond the physiological range during aging or under pathological conditions, it induces the shedding of its receptor PDGF receptor β (PDGFRβ) from cell membrane of the brain pericytes through matrix metalloproteinase 14 (MMP14), leading to pericyte loss and cerebrovascular impairment.
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DOI：
10.1038/s41583-020-0322-2
发表时间：
2020-08
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Kaplan L;Chow BW;Gu C
通讯作者：
Gu C
影响因子：
9.3
作者：
Elabi OF;Cunha JPMCM;Gaceb A;Fex M;Paul G
通讯作者：
Paul G
影响因子：
1.8
作者：
Bor, Amartuvshin;Nishijo, Muneko;Nishijo, Hisao
通讯作者：
Nishijo, Hisao
影响因子：
64.8
作者：
Conboy, IM;Conboy, MJ;Rando, TA
通讯作者：
Rando, TA
影响因子：
4.6
作者：
Bolte C;Flood HM;Ren X;Jagannathan S;Barski A;Kalin TV;Kalinichenko VV
通讯作者：
Kalinichenko VV