Arteriovenous malformation Map2k1 mutation affects vasculogenesis
© 2023. The Author(s)..
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 (R26GT-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 R26GT-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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
|---|---|
| Enthalten in: |
Scientific reports - 13(2023), 1 vom: 08. Juli, Seite 11074 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Sudduth, Christopher L [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
EC 2.7.12.2 |
|---|
| Anmerkungen: |
Date Completed 12.07.2023 Date Revised 21.02.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41598-023-35301-6 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM359235077 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM359235077 | ||
| 003 | DE-627 | ||
| 005 | 20240222091312.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41598-023-35301-6 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1301.xml |
| 035 | |a (DE-627)NLM359235077 | ||
| 035 | |a (NLM)37422456 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Sudduth, Christopher L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Arteriovenous malformation Map2k1 mutation affects vasculogenesis |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.07.2023 | ||
| 500 | |a Date Revised 21.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a 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 (R26GT-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 R26GT-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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 7 | |a Map2k1 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.7.12.2 |2 NLM | |
| 650 | 7 | |a MAP Kinase Kinase 1 |2 NLM | |
| 650 | 7 | |a EC 2.7.12.2 |2 NLM | |
| 700 | 1 | |a Smits, Patrick J |e verfasserin |4 aut | |
| 700 | 1 | |a Vivero, Matthew P |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Yu Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Ad, Michal |e verfasserin |4 aut | |
| 700 | 1 | |a Konczyk, Dennis J |e verfasserin |4 aut | |
| 700 | 1 | |a Bischoff, Joyce |e verfasserin |4 aut | |
| 700 | 1 | |a Warman, Matthew L |e verfasserin |4 aut | |
| 700 | 1 | |a Greene, Arin K |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Scientific reports |d 2011 |g 13(2023), 1 vom: 08. Juli, Seite 11074 |w (DE-627)NLM215703936 |x 2045-2322 |7 nnns |
| 773 | 1 | 8 | |g volume:13 |g year:2023 |g number:1 |g day:08 |g month:07 |g pages:11074 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41598-023-35301-6 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 13 |j 2023 |e 1 |b 08 |c 07 |h 11074 | ||