Molecular Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
J Cell Biol. 2019 Oct 7;218(10):3506-3525. doi: 10.1083/jcb.201807178. Epub 2019 Sep 20.
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 ()-deficient ( TG) mice than in control mice. Control mice showed increased numbers of pericytes in the ischemic lesion, whereas 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.
缺血性中风会导致血脑屏障 (BBB) 破裂，这是由于 BBB 成分的完整性受到严重破坏。最近的研究强调了周细胞在 PDGFRβ 上调触发的 BBB 功能修复过程中的重要性。在这里，我们表明，基底膜主要的肝素硫酸蛋白聚糖——聚糖蛋白，通过周细胞相互作用来帮助 BBB 的维持和修复。使用短暂性大脑中动脉闭塞模型，我们发现条件性缺失聚糖蛋白 () 的（ TG）小鼠比对照小鼠的梗死体积更大，BBB 渗漏更多。对照小鼠在缺血损伤部位显示出更多的周细胞，而 TG 小鼠则没有。在机制水平上，周细胞附着在重组聚糖蛋白 C 末端结构域 V（聚糖蛋白 DV，内皮抑制素）上。聚糖蛋白 DV 通过整合素 α5β1 部分增强 PDGF-BB 诱导的 PDGFRβ、SHP-2 和 FAK 的磷酸化，并促进周细胞迁移。因此，聚糖蛋白似乎通过 PDGFRβ 和整合素 α5β1 的协同作用来调节周细胞募集，以支持缺血性中风后 BBB 的维持和修复。
