Department of Ophthalmology, Shanghai Tenth People's Hospital, Shanghai, China.
Devers Eye Institute, Legacy Research Institute, Portland, Oregon, United States.
Invest Ophthalmol Vis Sci. 2021 Jan 4;62(1):26. doi: 10.1167/iovs.62.1.26.
Glia and their communication via connexin 43 (Cx43) gap junctions are known to mediate neurovascular coupling, a process driven by metabolic demand. However, it is unclear whether Cx43 mediated glial communication intermediates classical autoregulation. Here we used viral transfection and a glial fibrillary acidic protein (GFAP) promoter to downregulate glial Cx43 to evaluate its role in retinal vascular autoregulation to ocular perfusion pressure (OPP) reduction.
Adult rats were intravitreally injected with the viral active construct or a control. Three weeks after the injection, eyes were imaged using confocal scanning laser ophthalmoscopy before and during a period of OPP decrease induced by blood draw to lower blood pressure or by manometric IOP elevation. Vessel diameter responses to the OPP decrease were compared between Cx43-downregulated and control-injected eyes. The extent of Cx43 downregulation was evaluated by Western blot and immunohistochemistry.
In control eyes, the OPP decrease induced dilatation of arterioles, but not venules. In Cx43-downregulated eyes, Cx43 expression in whole retina was decreased by approximately 40%. In these eyes, the resting diameter of the venules increased significantly, but there was no effect on arterioles. In Cx43-downregulated eyes, vasoreactivity evoked by blood pressure lowering was significantly compromised in both arterioles (P = 0.005) and venules (P = 0.001). Cx43 downregulation did not affect the arteriole responses to IOP elevation, whereas the responses of the venules showed a significantly greater decrease in diameter (P < 0.001).
The downregulation of retinal Cx43 in GFAP-expressing cells compromises vasoreactivity of both arterioles and venules in response to an OPP decrease achieved via blood pressure lowering or IOP elevation. The results also suggest that Cx43-mediated glial communication actively regulates resting venular diameter.
已知神经胶质及其通过缝隙连接蛋白 43（Cx43）的通讯可介导神经血管耦合，该过程由代谢需求驱动。但是，尚不清楚 Cx43 介导的神经胶质通讯是否会影响经典的自动调节。在此，我们使用病毒转染和胶质纤维酸性蛋白（GFAP）启动子下调神经胶质 Cx43，以评估其在视网膜血管自动调节对眼灌注压（OPP）降低中的作用。
成年大鼠通过玻璃体内注射病毒活性构建物或对照物进行处理。注射后 3 周，通过共聚焦扫描激光检眼镜在眼底成像，同时通过采血降低血压或通过眼压升高进行 OPP 降低期间进行眼底成像。比较 Cx43 下调和对照物注射眼之间 OPP 降低时血管直径的反应。通过 Western blot 和免疫组化评估 Cx43 下调的程度。
在对照物眼中，OPP 降低会引起小动脉扩张，但不会引起小静脉扩张。在 Cx43 下调的眼中，整个视网膜中的 Cx43 表达降低了约 40％。在这些眼中，小静脉的静息直径显著增加，但对小动脉没有影响。在 Cx43 下调的眼中，通过降低血压诱发的血管反应性在小动脉（P = 0.005）和小静脉（P = 0.001）中均显著受损。Cx43 下调不影响小动脉对眼压升高的反应性，而小静脉的反应性表现出直径显著减小（P <0.001）。
GFAP 表达细胞中视网膜 Cx43 的下调会损害小动脉和小静脉对通过降低血压或升高眼压来实现的 OPP 降低的血管反应性。结果还表明，Cx43 介导的神经胶质通讯积极调节静息小静脉直径。
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