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RASA1 regulates the function of lymphatic vessel valves in mice
- Source :
- The Journal of clinical investigation. 127(7)
- Publication Year :
- 2016
-
Abstract
- Capillary malformation-arteriovenous malformation (CM-AVM) is a blood and lymphatic vessel (LV) disorder that is caused by inherited inactivating mutations of the RASA1 gene, which encodes p120 RasGAP (RASA1), a negative regulator of the Ras small GTP-binding protein. How RASA1 mutations lead to the LV leakage defects that occur in CM-AVM is not understood. Here, we report that disruption of the Rasa1 gene in adult mice resulted in loss of LV endothelial cells (LECs) specifically from the leaflets of intraluminal valves in collecting LVs. As a result, valves were unable to prevent fluid backflow and the vessels were ineffective pumps. Furthermore, disruption of Rasa1 in midgestation resulted in LEC apoptosis in developing LV valves and consequently failed LV valvulogenesis. Similar phenotypes were observed in induced RASA1-deficient adult mice and embryos expressing a catalytically inactive RASA1R780Q mutation. Thus, RASA1 catalytic activity is essential for the function and development of LV valves. These data provide a partial explanation for LV leakage defects and potentially other LV abnormalities observed in CM-AVM.
- Subjects :
- 0301 basic medicine
Mutation, Missense
Apoptosis
Negative regulator
03 medical and health sciences
Mice
0302 clinical medicine
Lymphatic vessel
Medicine
Missense mutation
Animals
Lymphatic Vessels
business.industry
RASA1 Gene
Endothelial Cells
Embryo
p120 GTPase Activating Protein
General Medicine
Phenotype
Mice, Mutant Strains
Cell biology
030104 developmental biology
medicine.anatomical_structure
business
030217 neurology & neurosurgery
Research Article
Subjects
Details
- ISSN :
- 15588238
- Volume :
- 127
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- The Journal of clinical investigation
- Accession number :
- edsair.doi.dedup.....bedb0734d38fd4d45843db0f392a1c40