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X-box binding protein 1-mediated COL4A1s secretion regulates communication between vascular smooth muscle and stem/progenitor cells

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Angshumonik Angbohang, Lei Huang, Yi Li, Yue Zhao, Yijie Gong, Yi Fu, Chenfeng Mao, Jose Morales, Peiyi Luo, Mazdak Ehteramyan, Yingtang Gao, Andriana Margariti, Wenduo Gu, Min Zhang, Alberto Smith, Ajay M. Shah, Tong Li, Wei Kong, Lingfang Zeng

Original languageEnglish
Article number100541
JournalJournal of Biological Chemistry
Published1 Jan 2021

Bibliographical note

Funding Information: Funding and additional information—This study was supported by funding from British Heart Foundation project grant PG16/13/ 32024 (L. Z.), the Natural Science Foundation of Tianjin City No.19JCYBJC26000 (T. L.), the Tianjin Third Central Hospital National Natural Science Foundation Incubation Project of China No.2019YNR1 (L. H.), the Tianjin municipal health and Health Committee Science and Technology Talent Cultivation Project of China No.KJ20008 (L. H.), and A. M. S. is supported by a British Heart Foundation Chair (CH/1999001/11735). The Tianjin Municipal Health and Health Committee Science and Technology Self Financing Project of China (No. ZD20001). Publisher Copyright: © 2021 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


Vascular smooth muscle cells (VSMCs) contribute to the deposition of extracellular matrix proteins (ECMs), including Type IV collagen, in the vessel wall. ECMs coordinate communication among different cell types, but mechanisms underlying this communication remain unclear. Our previous studies have demonstrated that X-box binding protein 1 (XBP1) is activated and contributes to VSMC phenotypic transition in response to vascular injury. In this study, we investigated the participation of XBP1 in the communication between VSMCs and vascular progenitor cells (VPCs). Immunofluorescence and immunohistology staining revealed that Xbp1 gene was essential for type IV collagen alpha 1 (COL4A1) expression during mouse embryonic development and vessel wall ECM deposition and stem cell antigen 1-positive (Sca1+)- VPC recruitment in response to vascular injury. The Western blot analysis elucidated an Xbp1 gene dose-dependent effect on COL4A1 expression and that the spliced XBP1 protein (XBP1s) increased protease-mediated COL4A1 degradation as revealed by Zymography. RT-PCR analysis revealed that XBP1s in VSMCs not only upregulated COL4A1/2 transcription but also induced the occurrence of a novel transcript variant, soluble type IV collagen alpha 1 (COL4A1s), in which the front part of exon 4 is joined with the rear part of exon 42. Chromatinimmunoprecipitation, DNA/protein pulldown and in vitro transcription demonstrated that XBP1s binds to exon 4 and exon 42, directing the transcription from exon 4 to exon 42. This leads to transcription complex bypassing the internal sequences, producing a shortened COL4A1s protein that increased Sca1+-VPC migration. Taken together, these results suggest that activated VSMCs may recruit Sca1+-VPCs via XBP1s-mediated COL4A1s secretion, leading to vascular injury repair or neointima formation.

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