From the Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine (T.Z., J.L., X.C., Y.K., Y.W., Z.Y., L.Z., Z.L., Y.Z.), Shanghai East Hospital, Tongji University School of Medicine, China.
Department of Cardiology (Q.Z., Y.L., J.P.), Shanghai East Hospital, Tongji University School of Medicine, China.
Arterioscler Thromb Vasc Biol. 2019 May;39(5):888-901. doi: 10.1161/ATVBAHA.118.312263.
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 cell-specific 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 (platelet-derived 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, VSMC-specific 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.
目的-转录因子 GATA（GATA 锌指转录因子家族）-6 在血管中高度表达，在球囊损伤的颈动脉中迅速下调，病毒递送 GATA-6 到血管中限制了新生内膜的形成，然而，其对血管平滑肌细胞（VSMC）表型状态的细胞特异性调节知之甚少，有助于新生内膜的形成。本研究旨在确定血管细胞特异性 GATA-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 GATA-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 GATA-6 缺失小鼠在动脉结扎和损伤后 VSMC 增殖减少，新生内膜形成减弱。血小板衍生生长因子（PDGF）-B 被鉴定为直接靶基因，内皮细胞-GATA-6-PDGF-B 途径以旁分泌方式调节 VSMC 增殖和迁移，从而控制新生内膜的形成。相比之下，VSMC 特异性 GATA-6 缺失促进损伤诱导的 VSMC 从收缩型向增殖型合成表型转化，导致新生内膜形成增加。CCN（富含半胱氨酸 61/结缔组织生长因子/肾母细胞瘤过表达家族）-5 被鉴定为一种新的靶基因，并且在小鼠中特异性 VSMC 过表达 CCN-5 可逆转 VSMC-GATA-6 缺失介导的细胞增殖和迁移增加，并最终减弱新生内膜的形成。结论-本研究为我们提供了直接的体内证据，证明 GATA-6 对 VSMC 表型状态、增殖和迁移的细胞谱系特异性调节，对新生内膜形成有贡献，这加深了我们对体内新生内膜增生的理解，同时也为未来的治疗干预提供了机会。
