Perlecan regulates pericyte dynamics in the maintenance and repair of the blood-brain barrier

Kuniyuki Nakamura, Tomoko Ikeuchi, Kazuki Nara, Craig S. Rhodes, Peipei Zhang, Yuta Chiba, Saiko Kazuno, Yoshiki Miura, Tetsuro Ago, Eri Arikawa-Hirasawa, Yoh Suke Mukouyama, Yoshihiko Yamada

Research output: Contribution to journalArticle

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Abstract

Ischemic stroke causes blood-brain barrier (BBB) breakdown due to significant damage to the integrity of BBB components. Recent studies have highlighted the importance of pericytes in the repair process of BBB functions triggered by PDGFRβ up-regulation. Here, we show that perlecan, a major heparan sulfate proteoglycan of basement membranes, aids in BBB maintenance and repair through pericyte interactions. Using a transient middle cerebral artery occlusion model, we found larger infarct volumes and more BBB leakage in conditional perlecan (Hspg2)-deficient (Hspg2-/--TG) mice than in control mice. Control mice showed increased numbers of pericytes in the ischemic lesion, whereas Hspg2-/--TG mice did not. At the mechanistic level, pericytes attached to recombinant perlecan C-terminal domain V (perlecan DV, endorepellin). Perlecan DV enhanced the PDGF-BB-induced phosphorylation of PDGFRβ, SHP-2, and FAK partially through integrin α5β1 and promoted pericyte migration. Perlecan therefore appears to regulate pericyte recruitment through the cooperative functioning of PDGFRβ and integrin α5β1 to support BBB maintenance and repair following ischemic stroke.

Original languageEnglish
Pages (from-to)3506-3525
Number of pages20
JournalThe Journal of cell biology
Volume218
Issue number10
DOIs
Publication statusPublished - Oct 7 2019

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Pericytes
Blood-Brain Barrier
Maintenance
Integrins
Stroke
Heparan Sulfate Proteoglycans
Middle Cerebral Artery Infarction
Basement Membrane
perlecan
Up-Regulation
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Perlecan regulates pericyte dynamics in the maintenance and repair of the blood-brain barrier. / Nakamura, Kuniyuki; Ikeuchi, Tomoko; Nara, Kazuki; Rhodes, Craig S.; Zhang, Peipei; Chiba, Yuta; Kazuno, Saiko; Miura, Yoshiki; Ago, Tetsuro; Arikawa-Hirasawa, Eri; Mukouyama, Yoh Suke; Yamada, Yoshihiko.

In: The Journal of cell biology, Vol. 218, No. 10, 07.10.2019, p. 3506-3525.

Research output: Contribution to journalArticle

Nakamura, K, Ikeuchi, T, Nara, K, Rhodes, CS, Zhang, P, Chiba, Y, Kazuno, S, Miura, Y, Ago, T, Arikawa-Hirasawa, E, Mukouyama, YS & Yamada, Y 2019, 'Perlecan regulates pericyte dynamics in the maintenance and repair of the blood-brain barrier', The Journal of cell biology, vol. 218, no. 10, pp. 3506-3525. https://doi.org/10.1083/jcb.201807178
Nakamura, Kuniyuki ; Ikeuchi, Tomoko ; Nara, Kazuki ; Rhodes, Craig S. ; Zhang, Peipei ; Chiba, Yuta ; Kazuno, Saiko ; Miura, Yoshiki ; Ago, Tetsuro ; Arikawa-Hirasawa, Eri ; Mukouyama, Yoh Suke ; Yamada, Yoshihiko. / Perlecan regulates pericyte dynamics in the maintenance and repair of the blood-brain barrier. In: The Journal of cell biology. 2019 ; Vol. 218, No. 10. pp. 3506-3525.
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