Cell-Specific Effects of GATA (GATA Zinc Finger Transcription Factor Family)-6 in Vascular Smooth Muscle and Endothelial Cells on Vascular Injury Neointimal Formation
Cell-Specific Effects of GATA (GATA Zinc Finger Transcription Factor Family)-6 in Vascular Smooth Muscle and Endothelial Cells on Vascular Injury Neointimal Formation
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GATA（GATA 锌指转录因子家族）-6 在血管平滑肌和内皮细胞中对血管损伤新内膜形成的细胞特异性影响
DOI：
10.1161/atvbaha.118.312263
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发表时间：
2019-05-01
影响因子：
8.7
通讯作者：
Zhang, Yuzhen
中科院分区：
文献类型：
--
作者：
Zhuang, Tao;Liu, Jie;Zhang, Yuzhen
加塔（加塔锌指转录因子家族）-6在血管中高表达，在球囊损伤的颈动脉中表达迅速下调，病毒介导的加塔-6对新生内膜的形成有一定的限制作用，但其对体内血管平滑肌细胞（VSMC）表型状态的特异性调控作用尚不清楚。本研究旨在确定血管细胞特异性加塔-6在体内结扎或损伤诱导的新生内膜增生中的作用。方法和结果-生成内皮细胞和VSMC特异性加塔-6缺失小鼠，结果表明与野生型同窝对照小鼠相比，内皮细胞特异性加塔-6缺失小鼠在动脉结扎和损伤后表现出VSMC增殖的显著降低和新生内膜形成的减弱。PDGF（plateletderivedgrowthfactor）-B是血管平滑肌细胞增殖的直接靶基因，血管内皮细胞-GATA-6-PDGF-B B通路以旁分泌方式调节血管平滑肌细胞的增殖和迁移，从而控制新生内膜的形成。相反，VSMC特异性加塔-6缺失可促进损伤诱导的VSMC从收缩型向增殖型转化，导致新生内膜形成增加。CCN-5（cysteine-rich 61/connective tissue growth factor/nephoblastoma overexpressed family）是一个新的靶基因，在小鼠中VSMC特异性CCN-5的过表达逆转了VSMC-GATA-6缺失介导的细胞增殖和迁移增加，并最终减弱了新生内膜的形成。结论：本研究为加塔-6细胞系特异性调节PDGF-B和CCN-5对VSMC表型、增殖和迁移的调控提供了直接的体内证据，促进了我们对体内新生内膜增生的认识，同时也为未来的治疗干预提供了机会。
Objective-Transcription factor GATA (GATA zinc finger transcription factor family)-6 is highly expressed in vessels and rapidly downregulated in balloon-injured carotid arteries and viral delivery of GATA-6 to the vessels limited the neointimal formation, however, little is known about its cell-specific regulation of in vivo vascular smooth muscle cell (VSMC) phenotypic state contributing to neointimal formation. This study aims to determine the role of vascular cellspecific GATA-6 in ligation-or injury-induced neointimal hyperplasia in vivo. Approach and Results-Endothelial cell and VSMC-specific GATA-6 deletion mice are generated, and the results indicate that endothelial cell-specific GATA-6 deletion mice exhibit significant decrease of VSMC proliferation and attenuation of neointimal formation after artery ligation and injury compared with the wild-type littermate control mice. PDGF (plateletderived growth factor)-B is identified as a direct target gene, and endothelial cell-GATA-6-PDGF-B pathway regulates VSMC proliferation and migration in a paracrine manner which controls the neointimal formation. In contrast, VSMCspecific GATA-6 deletion promotes injury-induced VSMC transformation from contractile to proliferative synthetic phenotype leading to increased neointimal formation. CCN (cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed family)-5 is identified as a novel target gene, and VSMC-specific CCN-5 overexpression in mice reverses the VSMC-GATA-6 deletion-mediated increased cell proliferation and migration and finally attenuates the neointimal formation. Conclusions-This study gives us a direct in vivo evidence of GATA-6 cell lineage-specific regulation of PDGF-B and CCN-5 on VSMC phenotypic state, proliferation and migration contributing to neointimal formation, which advances our understanding of in vivo neointimal hyperplasia, meanwhile also provides opportunities for future therapeutic interventions.