VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells
Summary: The formation of new vessels requires a tight synchronization between proliferation, differentiation, and sprouting. However, how these processes are differentially activated, often by neighboring endothelial cells (ECs), remains unclear. Here, we identify cell cycle progression as a regula...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-06-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721006203 |
| _version_ | 1818457525536686080 |
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| author | Ayelet Jerafi-Vider Ivan Bassi Noga Moshe Yaara Tevet Gideon Hen Daniel Splittstoesser Masahiro Shin Nathan D. Lawson Karina Yaniv |
| author_facet | Ayelet Jerafi-Vider Ivan Bassi Noga Moshe Yaara Tevet Gideon Hen Daniel Splittstoesser Masahiro Shin Nathan D. Lawson Karina Yaniv |
| author_sort | Ayelet Jerafi-Vider |
| collection | DOAJ |
| description | Summary: The formation of new vessels requires a tight synchronization between proliferation, differentiation, and sprouting. However, how these processes are differentially activated, often by neighboring endothelial cells (ECs), remains unclear. Here, we identify cell cycle progression as a regulator of EC sprouting and differentiation. Using transgenic zebrafish illuminating cell cycle stages, we show that venous and lymphatic precursors sprout from the cardinal vein exclusively in G1 and reveal that cell-cycle arrest is induced in these ECs by overexpression of p53 and the cyclin-dependent kinase (CDK) inhibitors p27 and p21. We further demonstrate that, in vivo, forcing G1 cell-cycle arrest results in enhanced vascular sprouting. Mechanistically, we identify the mitogenic VEGFC/VEGFR3/ERK axis as a direct inducer of cell-cycle arrest in ECs and characterize the cascade of events that render “sprouting-competent” ECs. Overall, our results uncover a mechanism whereby mitogen-controlled cell-cycle arrest boosts sprouting, raising important questions about the use of cell cycle inhibitors in pathological angiogenesis and lymphangiogenesis. |
| first_indexed | 2024-12-14T22:43:57Z |
| format | Article |
| id | doaj.art-652f9d960400488a9c06396894b1e936 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-14T22:43:57Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-652f9d960400488a9c06396894b1e9362022-12-21T22:44:53ZengElsevierCell Reports2211-12472021-06-013511109255VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cellsAyelet Jerafi-Vider0Ivan Bassi1Noga Moshe2Yaara Tevet3Gideon Hen4Daniel Splittstoesser5Masahiro Shin6Nathan D. Lawson7Karina Yaniv8Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, IsraelDepartment of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USADepartment of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel; Corresponding authorSummary: The formation of new vessels requires a tight synchronization between proliferation, differentiation, and sprouting. However, how these processes are differentially activated, often by neighboring endothelial cells (ECs), remains unclear. Here, we identify cell cycle progression as a regulator of EC sprouting and differentiation. Using transgenic zebrafish illuminating cell cycle stages, we show that venous and lymphatic precursors sprout from the cardinal vein exclusively in G1 and reveal that cell-cycle arrest is induced in these ECs by overexpression of p53 and the cyclin-dependent kinase (CDK) inhibitors p27 and p21. We further demonstrate that, in vivo, forcing G1 cell-cycle arrest results in enhanced vascular sprouting. Mechanistically, we identify the mitogenic VEGFC/VEGFR3/ERK axis as a direct inducer of cell-cycle arrest in ECs and characterize the cascade of events that render “sprouting-competent” ECs. Overall, our results uncover a mechanism whereby mitogen-controlled cell-cycle arrest boosts sprouting, raising important questions about the use of cell cycle inhibitors in pathological angiogenesis and lymphangiogenesis.http://www.sciencedirect.com/science/article/pii/S2211124721006203 |
| spellingShingle | Ayelet Jerafi-Vider Ivan Bassi Noga Moshe Yaara Tevet Gideon Hen Daniel Splittstoesser Masahiro Shin Nathan D. Lawson Karina Yaniv VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells Cell Reports |
| title | VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells |
| title_full | VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells |
| title_fullStr | VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells |
| title_full_unstemmed | VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells |
| title_short | VEGFC/FLT4-induced cell-cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells |
| title_sort | vegfc flt4 induced cell cycle arrest mediates sprouting and differentiation of venous and lymphatic endothelial cells |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721006203 |
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