Arteriovenous malformation Map2k1 mutation affects vasculogenesis
Abstract Somatic activating MAP2K1 mutations in endothelial cells (ECs) cause extracranial arteriovenous malformation (AVM). We previously reported the generation of a mouse line allowing inducible expression of constitutively active MAP2K1 (p.K57N) from the Rosa locus (R26 GT-Map2k1-GFP/+) and show...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-35301-6 |
| _version_ | 1827905512371388416 |
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| author | Christopher L. Sudduth Patrick J. Smits Matthew P. Vivero Yu Sheng Cheng Michal Ad Dennis J. Konczyk Joyce Bischoff Matthew L. Warman Arin K. Greene |
| author_facet | Christopher L. Sudduth Patrick J. Smits Matthew P. Vivero Yu Sheng Cheng Michal Ad Dennis J. Konczyk Joyce Bischoff Matthew L. Warman Arin K. Greene |
| author_sort | Christopher L. Sudduth |
| collection | DOAJ |
| description | Abstract Somatic activating MAP2K1 mutations in endothelial cells (ECs) cause extracranial arteriovenous malformation (AVM). We previously reported the generation of a mouse line allowing inducible expression of constitutively active MAP2K1 (p.K57N) from the Rosa locus (R26 GT-Map2k1-GFP/+) and showed, using Tg-Cdh5CreER, that EC expression of mutant MAP2K1 is sufficient for the development of vascular malformations in the brain, ear, and intestines. To gain further insight into the mechanism by which mutant MAP2K1 drives AVM development, we induced MAP2K1 (p.K57N) expression in ECs of postnatal-day-1 pups (P1) and investigated the changes in gene expression in P9 brain ECs by RNA-seq. We found that over-expression of MAP2K1 altered the transcript abundance of > 1600 genes. Several genes had > 20-fold changes between MAP2K1 expressing and wild-type ECs; the highest were Col15a1 (39-fold) and Itgb3 (24-fold). Increased expression of COL15A1 in R26 GT-Map2k1-GFP/+; Tg-Cdh5CreER +/− brain ECs was validated by immunostaining. Ontology showed that differentially expressed genes were involved in processes important for vasculogenesis (e.g., cell migration, adhesion, extracellular matrix organization, tube formation, angiogenesis). Understanding how these genes and pathways contribute to AVM formation will help identify targets for therapeutic intervention. |
| first_indexed | 2024-03-13T00:42:41Z |
| format | Article |
| id | doaj.art-91ceb84d79d14d2ea4b48451f54c8f3a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-13T00:42:41Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-91ceb84d79d14d2ea4b48451f54c8f3a2023-07-09T11:12:55ZengNature PortfolioScientific Reports2045-23222023-07-011311810.1038/s41598-023-35301-6Arteriovenous malformation Map2k1 mutation affects vasculogenesisChristopher L. Sudduth0Patrick J. Smits1Matthew P. Vivero2Yu Sheng Cheng3Michal Ad4Dennis J. Konczyk5Joyce Bischoff6Matthew L. Warman7Arin K. Greene8Department of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical SchoolVascular Biology Program, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Orthopedic Surgery, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Plastic and Oral Surgery, Boston Children’s Hospital, Harvard Medical SchoolAbstract Somatic activating MAP2K1 mutations in endothelial cells (ECs) cause extracranial arteriovenous malformation (AVM). We previously reported the generation of a mouse line allowing inducible expression of constitutively active MAP2K1 (p.K57N) from the Rosa locus (R26 GT-Map2k1-GFP/+) and showed, using Tg-Cdh5CreER, that EC expression of mutant MAP2K1 is sufficient for the development of vascular malformations in the brain, ear, and intestines. To gain further insight into the mechanism by which mutant MAP2K1 drives AVM development, we induced MAP2K1 (p.K57N) expression in ECs of postnatal-day-1 pups (P1) and investigated the changes in gene expression in P9 brain ECs by RNA-seq. We found that over-expression of MAP2K1 altered the transcript abundance of > 1600 genes. Several genes had > 20-fold changes between MAP2K1 expressing and wild-type ECs; the highest were Col15a1 (39-fold) and Itgb3 (24-fold). Increased expression of COL15A1 in R26 GT-Map2k1-GFP/+; Tg-Cdh5CreER +/− brain ECs was validated by immunostaining. Ontology showed that differentially expressed genes were involved in processes important for vasculogenesis (e.g., cell migration, adhesion, extracellular matrix organization, tube formation, angiogenesis). Understanding how these genes and pathways contribute to AVM formation will help identify targets for therapeutic intervention.https://doi.org/10.1038/s41598-023-35301-6 |
| spellingShingle | Christopher L. Sudduth Patrick J. Smits Matthew P. Vivero Yu Sheng Cheng Michal Ad Dennis J. Konczyk Joyce Bischoff Matthew L. Warman Arin K. Greene Arteriovenous malformation Map2k1 mutation affects vasculogenesis Scientific Reports |
| title | Arteriovenous malformation Map2k1 mutation affects vasculogenesis |
| title_full | Arteriovenous malformation Map2k1 mutation affects vasculogenesis |
| title_fullStr | Arteriovenous malformation Map2k1 mutation affects vasculogenesis |
| title_full_unstemmed | Arteriovenous malformation Map2k1 mutation affects vasculogenesis |
| title_short | Arteriovenous malformation Map2k1 mutation affects vasculogenesis |
| title_sort | arteriovenous malformation map2k1 mutation affects vasculogenesis |
| url | https://doi.org/10.1038/s41598-023-35301-6 |
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