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J Clin Invest. 2017 Jun 30;127(7):2569-2585. doi: 10.1172/JCI89607. Epub 2017 May 22.

RASA1 regulates the function of lymphatic vessel valves in mice.

Author information

1
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
2
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, USA.

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.

PMID:
28530642
PMCID:
PMC5490778
DOI:
10.1172/JCI89607
[Indexed for MEDLINE]
Free PMC Article

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