The Sarcoglycan complex is expressed in the cerebrovascular system and is specifically regulated by astroglial Cx30 channels

Astrocytes, the most prominent glial cell type in the brain, send specialized processes called endfeet around blood vessels and express a large molecular repertoire regulating the cerebrovascular system physiology. One of the most striking properties of astrocyte endfeet is their enrichment in gap junction protein Connexin 43 and 30 (Cx43 and Cx30) allowing in particular for direct intercellular trafficking of ions and small signaling molecules through perivascular astroglial networks. In this study, we addressed the specific role of Cx30 at the gliovascular interface. Using an inactivation mouse model for Cx30 (Cx30Δ/Δ), we showed that absence of Cx30 does not affect blood-brain barrier (BBB) organization and permeability. However, it results in the cerebrovascular fraction, in a strong upregulation of Sgcg encoding g-Sarcoglycan (SG), a member of the Dystrophin-associated protein complex (DAPC) connecting cytoskeleton and the extracellular matrix. The same molecular event occurs in Cx30T5M/T5M mutated mice, where Cx30 channels are closed, demonstrating that Sgcg regulation relied on Cx30 channel functions. We further characterized the cerebrovascular Sarcoglycan complex (SGC) and showed the presence of alpha-, beta-, delta-, gamma-, epsilon-, and zeta- SG, as well as Sarcospan. Altogether, our results suggest that the Sarcoglycan complex is present in the cerebrovascular system, and that expression of one of its members, g-Sarcoglycan, depends on Cx30 channels. As described in skeletal muscles, the SGC may contribute to membrane stabilization and signal transduction in the cerebrovascular system, which may therefore be regulated by Cx30 channel-mediated functions. Comparison of 3-month-old Cx30 deleted mice against WT genetic background.星形胶质细胞是大脑中最主要的胶质细胞类型，其伸出名为终足（endfeet）的特化突起包裹血管，并表达大量分子以调控脑血管系统的生理功能。星形胶质细胞终足最显著的特征之一，是其富含间隙连接蛋白Connexin 43与30（Cx43、Cx30），这使得离子与小型信号分子可通过血管周胶质网络直接进行细胞间转运。 本研究聚焦于Cx30在胶质血管界面（gliovascular interface）的特异性功能。本研究使用Cx30纯合失活小鼠模型（Cx30Δ/Δ），证实Cx30缺失不会影响血脑屏障（blood-brain barrier, BBB）的结构与通透性。然而其会在脑血管组分中引发编码γ-肌聚糖（g-Sarcoglycan, SG）的Sgcg基因显著上调——γ-肌聚糖是连接细胞骨架与细胞外基质的肌营养不良蛋白关联复合物（Dystrophin-associated protein complex, DAPC）的成员之一。在Cx30T5M/T5M突变小鼠（该模型中Cx30通道处于关闭状态）中也观测到了相同的分子事件，这表明Sgcg的调控依赖于Cx30通道的功能。 本研究进一步对脑血管系统中的肌聚糖复合物（Sarcoglycan complex, SGC）进行了表征，证实其包含α-、β-、δ-、γ-、ε-及ζ-肌聚糖，同时还存在Sarcospan。综上，本研究结果表明，脑血管系统中存在肌聚糖复合物，且其成员之一γ-肌聚糖的表达依赖于Cx30通道。正如在骨骼肌中的研究结论一致，脑血管系统中的肌聚糖复合物（SGC）可能参与细胞膜稳定与信号转导过程，因此其功能可受Cx30通道介导的调控机制所影响。本研究对3月龄Cx30敲除小鼠与野生型（WT）遗传背景小鼠进行了对比分析。