RASA1 regulates the function of lymphatic vessel valves in mice

The Journal of Clinical Investigation
Philip E LapinskiPhilip D King

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.

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Citations

Nov 11, 2017·Disease Models & Mechanisms·Xin GengR Sathish Srinivasan
Jun 12, 2019·The Journal of Clinical Investigation·Di ChenPhilip D King
May 29, 2018·Biomechanics and Modeling in Mechanobiology·Matthew BallardAlexander Alexeev
Aug 23, 2020·Cancers·Drishya IyerJoshua P Scallan
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Dec 3, 2020·Frontiers in Cardiovascular Medicine·Khoa Bui, Young-Kwon Hong
Mar 27, 2021·Current Opinion in Hematology·Ondine Cleaver
Mar 27, 2021·Current Opinion in Hematology·Ondine Cleaver
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Jul 10, 2021·Cellular and Molecular Life Sciences : CMLS·Xin GengR Sathish Srinivasan
Jul 16, 2021·The Journal of Clinical Investigation·Joshua P ScallanYing Yang
Aug 10, 2021·Journal of Fluid Mechanics·Ki Tae WolfAlexander Alexeev

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Methods Mentioned

BETA
transgenic

Related Concepts

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