Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice
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Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice Quang Linh Nguyen1,2 · Noriko Okuno1 · Takeru Hamashima1 · Son Tung Dang1 · Miwa Fujikawa1 · Yoko Ishii3 · Atsushi Enomoto4 · Takakuni Maki5 · Hoang Ngoc Nguyen2 · Van Tuyen Nguyen2 · Toshihiko Fujimori6 · Hisashi Mori7 · Johanna Andrae8 · Christer Betsholtz8,9 · Keizo Takao10 · Seiji Yamamoto1 · Masakiyo Sasahara1 Received: 10 June 2020 / Accepted: 1 September 2020 © Springer Nature B.V. 2020
Abstract Blood–brain barrier (BBB) dysfunction underlies the pathogenesis of many neurological diseases. Platelet-derived growth factor receptor-alpha (PDGFRα) induces hemorrhagic transformation (HT) downstream of tissue plasminogen activator in thrombolytic therapy of acute stroke. Thus, PDGFs are attractive therapeutic targets for BBB dysfunction. In the present study, we examined the role of PDGF signaling in the process of tissue remodeling after middle cerebral arterial occlusion (MCAO) in mice. Firstly, we found that imatinib increased lesion size after permanent MCAO in wild-type mice. Moreover, imatinib-induced HT only when administrated in the subacute phase of MCAO, but not in the acute phase. Secondly, we generated genetically mutated mice (C-KO mice) that showed decreased expression of perivascular PDGFRα. Additionally, transient MCAO experiments were performed in these mice. We found that the ischemic lesion size was not affected; however, the recruitment of PDGFRα/type I collagen-expressing perivascular cells was significantly downregulated, and HT and IgG leakage was augmented only in the subacute phase of stroke in C-KO mice. In both experiments, we found that the expression of tight junction proteins and PDGFRβ-expressing pericyte coverage was not significantly affected in imatinib-treated mice and in C-KO mice. The specific implication of PDGFRα signaling was suggestive of protective effects against BBB dysfunction during the subacute phase of stroke. Vascular TGF-β1 expression was downregulated in both imatinib-treated and C-KO mice, along with sustained levels of MMP9. Therefore, PDGFRα effects may be mediated by TGF-β1 which exerts potent protective effects in the BBB. Keywords Ischemic stroke · Hemorrhagic transformation · Perivascular fibroblast-like cells · PDGF receptor-alpha · Imatinib
Introduction Dysfunction of the blood–brain barrier (BBB) is critically involved in the pathogenesis of many neurological diseases including acute cerebrovascular and chronic degenerative diseases. Therefore, the BBB is an important therapeutic target for such intractable neurological diseases [1]. BBB Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09742-w) contains supplementary material, which is available to authorized users. * Seiji Yamamoto [email protected]‑toyama.ac.jp * Masakiyo Sasahara [email protected]‑toyama.ac.jp Extended author information available on the last page of the article
dysfunction following ischemic stroke mediates brain edema and hemorrhagi
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