miR-137 and its target T-type CaV 3.1 channel modulate dedifferentiation and proliferation of cerebrovascular smooth muscle cells in simulated microgravity rats by regulating calcineurin/NFAT pathway.
miR-137 and its target T-type CaV 3.1 channel modulate dedifferentiation and proliferation of cerebrovascular smooth muscle cells in simulated microgravity rats by regulating calcineurin/NFAT pathway.
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miR-137及其靶标T型CaV3.1通道通过调节钙调神经磷酸酶/NFAT通路调节模拟微重力大鼠脑血管平滑肌细胞的去分化和增殖
DOI：
10.1111/cpr.12774
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发表时间：
2020
影响因子：
8.5
通讯作者：
Xie Man-Jiang
中科院分区：
文献类型：
--
作者：
Zhang Bin;Chen Li;Bai Yun-Gang;Song Ji-Bo;Cheng Jiu-Hua;Ma Hong-Zhe;Ma Jin;Xie Man-Jiang
目的飞行后立位耐力不耐受被认为是微重力暴露后的主要不良反应，脑血管适应在其中起着关键作用。我们先前的研究表明，血管平滑肌细胞（VSMCs）的去分化可能是模拟微重力下脑血管适应的关键因素之一。本研究的目的是证实这一概念，并阐明潜在的mechanism.Materials and MethodsSprague道利大鼠进行了28天后肢卸载，以模拟微重力暴露。通过超微结构分析和收缩/合成标记物检测来评估VSMC的去分化。T-型CaV3.1通道的作用通过评估其阻断作用来揭示。MiR-137通过荧光素酶测定被鉴定为CaV 3.1通道的上游，并通过功能获得/丧失方法进行研究。通过检测钙调神经磷酸酶活性和活化T淋巴细胞核因子（NFAT）核转位，研究了CaV3.1通道下游的NFAT通路。T-型CaV3.1通道促进VSMC的去分化和增殖。miR-137和calcineurin/NFATc 3通路分别是T‐type CaV 3. 1通道调控VSMCs去分化和增殖的上下游信号通路。结论miR-137及其靶T‐type CaV 3. 1通道通过调节calcineurin/NFATc 3通路调控模拟微重力下大鼠脑VSMCs的去分化和增殖。
ObjectivesPostflight orthostatic intolerance has been regarded as a major adverse effect after microgravity exposure, in which cerebrovascular adaptation plays a critical role. Our previous finding suggested that dedifferentiation of vascular smooth muscle cells (VSMCs) might be one of the key contributors to cerebrovascular adaptation under simulated microgravity. This study was aimed to confirm this concept and elucidate the underlying mechanisms.Materials and MethodsSprague Dawley rats were subjected to 28‐day hindlimb‐unloading to simulate microgravity exposure. VSMC dedifferentiation was evaluated by ultrastructural analysis and contractile/synthetic maker detection. The role of T‐type CaV3.1 channel was revealed by assessing its blocking effects. MiR‐137 was identified as the upstream of CaV3.1 channel by luciferase assay and investigated by gain/loss‐of‐function approaches. Calcineurin/nuclear factor of activated T lymphocytes (NFAT) pathway, the downstream of CaV3.1 channel, was investigated by detecting calcineurin activity and NFAT nuclear translocation.ResultsSimulated microgravity induced the dedifferentiation and proliferation in rat cerebral VSMCs. T‐type CaV3.1 channel promoted the dedifferentiation and proliferation of VSMC. MiR‐137 and calcineurin/NFATc3 pathway were the upstream and downstream signalling of T‐type CaV3.1 channel in modulating the dedifferentiation and proliferation of VSMCs, respectively.ConclusionsThe present work demonstrated that miR‐137 and its target T‐type CaV3.1 channel modulate the dedifferentiation and proliferation of rat cerebral VSMCs under simulated microgravity by regulating calcineurin/NFATc3 pathway.