Cell-Specific Effects of GATA (GATA Zinc Finger Transcription Factor Family)-6 in Vascular Smooth Muscle and Endothelial Cells on Vascular Injury Neointimal Formation

Tao Zhuang, Jie Liu, Xiaoli Chen, Jingjiang Pi, Yashu Kuang, Yanfang Wang, Brain Tomlinson, Paul Chan, Qi Zhang, Ying Li, Zuoren Yu, Xiangjian Zheng, Muredach Reilly, Edward Morrisey, Lin Zhang, Zhongmin Liu, Yuzhen Zhang

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)888-901
Number of pages14
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume39
Issue number5
DOIs
Publication statusPublished - May 1 2019

Keywords

  • carotid arteries
  • cell lineage
  • endothelial cells
  • hyperplasia
  • transcription factors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Zhuang, T., Liu, J., Chen, X., Pi, J., Kuang, Y., Wang, Y., Tomlinson, B., Chan, P., Zhang, Q., Li, Y., Yu, Z., Zheng, X., Reilly, M., Morrisey, E., Zhang, L., Liu, Z., & Zhang, Y. (2019). Cell-Specific Effects of GATA (GATA Zinc Finger Transcription Factor Family)-6 in Vascular Smooth Muscle and Endothelial Cells on Vascular Injury Neointimal Formation. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(5), 888-901. https://doi.org/10.1161/ATVBAHA.118.312263