TY - JOUR
T1 - Perlecan regulates pericyte dynamics in the maintenance and repair of the blood-brain barrier
AU - Nakamura, Kuniyuki
AU - Ikeuchi, Tomoko
AU - Nara, Kazuki
AU - Rhodes, Craig S.
AU - Zhang, Peipei
AU - Chiba, Yuta
AU - Kazuno, Saiko
AU - Miura, Yoshiki
AU - Ago, Tetsuro
AU - Arikawa-Hirasawa, Eri
AU - Mukouyama, Yoh Suke
AU - Yamada, Yoshihiko
N1 - Funding Information:
This study was supported in part by the Intramural Research Program of NIDCR, National Institutes of Health (DE000485-27 to Y. Yamada), and by the NIDCR Gene Transfer Core Facility (ZIC DE000744-04). K. Nakamura was supported by a Research Fellowship from the Uehara Memorial Foundation, a grant from SENSHIN Medical Research Foundation, and a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (19K09511). E. Arikawa-Hirasawa was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (15K09326). The authors declare no competing financial interests.
Publisher Copyright:
© 2019 Rockefeller University Press. All rights reserved.
PY - 2019/10/7
Y1 - 2019/10/7
N2 - 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 upregulation. 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.
AB - 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 upregulation. 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.
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U2 - 10.1083/JCB.201807178
DO - 10.1083/JCB.201807178
M3 - Article
C2 - 31541017
AN - SCOPUS:85072993865
VL - 218
SP - 3506
EP - 3525
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 10
ER -
