Control of Angiogenesis via a VHL/miR-212/132 Axis
A common feature of tumorigenesis is the upregulation of angiogenesis pathways in order to supply nutrients via the blood for the growing tumor. Understanding how cells promote angiogenesis and how to control these processes pharmaceutically are of great clinical interest. Clear cell renal cell carc...
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| Format: | Article |
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MDPI AG
2020-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/4/1017 |
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| author | Zhiyong Lei Timothy D. Klasson Maarten M. Brandt Glenn van de Hoek Ive Logister Caroline Cheng Pieter A. Doevendans Joost P. G. Sluijter Rachel H. Giles |
| author_facet | Zhiyong Lei Timothy D. Klasson Maarten M. Brandt Glenn van de Hoek Ive Logister Caroline Cheng Pieter A. Doevendans Joost P. G. Sluijter Rachel H. Giles |
| author_sort | Zhiyong Lei |
| collection | DOAJ |
| description | A common feature of tumorigenesis is the upregulation of angiogenesis pathways in order to supply nutrients via the blood for the growing tumor. Understanding how cells promote angiogenesis and how to control these processes pharmaceutically are of great clinical interest. Clear cell renal cell carcinoma (ccRCC) is the most common form of sporadic and inherited kidney cancer which is associated with excess neovascularization. ccRCC is highly associated with biallelic mutations in the von Hippel–Lindau (VHL) tumor suppressor gene. Although upregulation of the miR-212/132 family and disturbed VHL signaling have both been linked with angiogenesis, no evidence of a possible connection between the two has yet been made. We show that miRNA-212/132 levels are increased after loss of functional pVHL, the protein product of the VHL gene, in vivo and in vitro. Furthermore, we show that blocking miRNA-212/132 with anti-miRs can significantly alleviate the excessive vascular branching phenotype characteristic of vhl<sup>−/−</sup> mutant zebrafish. Moreover, using human umbilical vascular endothelial cells (HUVECs) and an endothelial cell/pericyte coculture system, we observed that VHL knockdown promotes endothelial cells neovascularization capacity in vitro, an effect which can be inhibited by anti-miR-212/132 treatment. Taken together, our results demonstrate an important role for miRNA-212/132 in angiogenesis induced by loss of VHL. Intriguingly, this also presents a possibility for the pharmaceutical manipulation of angiogenesis by modulating levels of MiR212/132. |
| first_indexed | 2024-03-10T20:22:32Z |
| format | Article |
| id | doaj.art-ba0ba3c2059248c5a3dfae6197a9f0f8 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T20:22:32Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-ba0ba3c2059248c5a3dfae6197a9f0f82023-11-19T22:07:00ZengMDPI AGCells2073-44092020-04-0194101710.3390/cells9041017Control of Angiogenesis via a VHL/miR-212/132 AxisZhiyong Lei0Timothy D. Klasson1Maarten M. Brandt2Glenn van de Hoek3Ive Logister4Caroline Cheng5Pieter A. Doevendans6Joost P. G. Sluijter7Rachel H. Giles8Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The NetherlandsDepartment of Nephrology & Hypertension, Division Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The NetherlandsExperimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The NetherlandsDepartment of Medical Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The NetherlandsDepartment of Nephrology & Hypertension, Division Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The NetherlandsDepartment of Nephrology & Hypertension, Division Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The NetherlandsDepartment of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The NetherlandsDepartment of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The NetherlandsDepartment of Nephrology & Hypertension, Division Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The NetherlandsA common feature of tumorigenesis is the upregulation of angiogenesis pathways in order to supply nutrients via the blood for the growing tumor. Understanding how cells promote angiogenesis and how to control these processes pharmaceutically are of great clinical interest. Clear cell renal cell carcinoma (ccRCC) is the most common form of sporadic and inherited kidney cancer which is associated with excess neovascularization. ccRCC is highly associated with biallelic mutations in the von Hippel–Lindau (VHL) tumor suppressor gene. Although upregulation of the miR-212/132 family and disturbed VHL signaling have both been linked with angiogenesis, no evidence of a possible connection between the two has yet been made. We show that miRNA-212/132 levels are increased after loss of functional pVHL, the protein product of the VHL gene, in vivo and in vitro. Furthermore, we show that blocking miRNA-212/132 with anti-miRs can significantly alleviate the excessive vascular branching phenotype characteristic of vhl<sup>−/−</sup> mutant zebrafish. Moreover, using human umbilical vascular endothelial cells (HUVECs) and an endothelial cell/pericyte coculture system, we observed that VHL knockdown promotes endothelial cells neovascularization capacity in vitro, an effect which can be inhibited by anti-miR-212/132 treatment. Taken together, our results demonstrate an important role for miRNA-212/132 in angiogenesis induced by loss of VHL. Intriguingly, this also presents a possibility for the pharmaceutical manipulation of angiogenesis by modulating levels of MiR212/132.https://www.mdpi.com/2073-4409/9/4/1017VHL loss of functionmicroRNA-212/132angiogenesis |
| spellingShingle | Zhiyong Lei Timothy D. Klasson Maarten M. Brandt Glenn van de Hoek Ive Logister Caroline Cheng Pieter A. Doevendans Joost P. G. Sluijter Rachel H. Giles Control of Angiogenesis via a VHL/miR-212/132 Axis Cells VHL loss of function microRNA-212/132 angiogenesis |
| title | Control of Angiogenesis via a VHL/miR-212/132 Axis |
| title_full | Control of Angiogenesis via a VHL/miR-212/132 Axis |
| title_fullStr | Control of Angiogenesis via a VHL/miR-212/132 Axis |
| title_full_unstemmed | Control of Angiogenesis via a VHL/miR-212/132 Axis |
| title_short | Control of Angiogenesis via a VHL/miR-212/132 Axis |
| title_sort | control of angiogenesis via a vhl mir 212 132 axis |
| topic | VHL loss of function microRNA-212/132 angiogenesis |
| url | https://www.mdpi.com/2073-4409/9/4/1017 |
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