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HIF1A promotes miR-210/miR-424 transcription to modulate the angiogenesis in HUVECs and HDMECs via sFLT1 under hypoxic stress

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Abstract

Angiogenesis is a critical process during human skin wound healing. However, hypoxia might lead to the dysfunction of the cellular interplay of endothelial cells and subcutaneous fibroblasts, resulting in the deregulation of angiogenesis. HIF1A is a key regulatory of the recovery of intracellular homeostasis under hypoxia. In the present study, the detailed role and mechanism of HIF1A in the angiogenesis under hypoxia were investigated. Via bioinformatic analyses on microarray profiles (GSE1041 and GSE17944), solube fms-related tyrosine kinase 1 (sFLT1, also known as sVEGFR1) and miR-210/miR-424 might be involved in HIF1A function on the angiogenesis under hypoxia in human umbilical vascular endothelium cells (HUVECs) and human dermal microvascular endothelial cells (HDMECs). In the present study, we identified sFLT1 as a downregulated gene in response to hypoxia and HIF1A overexpression in HUVECs and HDMECs. sFLT1 overexpression inhibited the capacity of migration and angiogenesis and significantly reversed the inducible effects of HIF1A on the migration and angiogenesis in both cell lines. miR-210 and miR-424 were upregulated by hypoxia and targeted sFLT1 3′-UTR to negatively modulate its expression. HIF1A modulated sFLT1 expression, VEGF signaling, and the migration and angiogenesis in HUVECs and HDMECs via miR-210/miR-424. Regarding the molecular mechanism, HIF1A bound the promoter region of miR-210 and miR-424 to activate their transcription, while miR-210/miR-424 bound sFLT1 3′-UTR to suppress its expression. In summary, HIF1A/miR-210/miR-424/sFLT1 axis modulates the angiogenesis in HUVECs and HDMECs upon hypoxic condition via VEGF signaling.

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Funding

This study was supported by the National Natural Science Foundation of China (No. 81501709) and Natural Science Foundation of Hunan Province, China (No. 2021JJ30928).

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Authors and Affiliations

  1. Department of Plastic and Aesthetic (Burn) Surgery, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Furong District, Changsha, 410011, Hunan, China

    Haifu Zhao, Xiancheng Wang & Bairong Fang

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  1. Haifu Zhao
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  2. Xiancheng Wang
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  3. Bairong Fang
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by BF, XW and HZ. The first draft of the manuscript was written by HZ. All authors read and approved the final manuscript.

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Correspondence to Bairong Fang.

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11010_2022_4428_MOESM1_ESM.tif

Supplementary file1 (TIF 147 kb) Fig. S1 HUVEC cells were co-transfected with NC (negative control) or HIF1A-overexpressing vector and wt-miR-210/miR-424 or mut-miR-210/miR-424 and examined for the promoter activity. **P < 0.01, compared to NC group

Supplementary file2 (DOCX 19 kb)

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Zhao, H., Wang, X. & Fang, B. HIF1A promotes miR-210/miR-424 transcription to modulate the angiogenesis in HUVECs and HDMECs via sFLT1 under hypoxic stress. Mol Cell Biochem 477, 2107–2119 (2022). https://doi.org/10.1007/s11010-022-04428-x

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  • DOI: https://doi.org/10.1007/s11010-022-04428-x

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