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Cited by 71Lymphatic System and DiseasesVascular Malformations and HemangiomasLymphatic Disorders and Treatments

RASA1 regulates the function of lymphatic vessel valves in mice

Open access
Lapinski, Philip E., Lubeck, Beth A., Chen, Di, Doosti, Abbas, Zawieja, Scott D., Davis, Michael J., King, Philip D.·2017·Journal of Clinical Investigation
DOI 10.1172/jci89607PMC PMC5490778
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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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  • Valve defects lead to increased back leak and an increased ΔP required for closure, even to the point where they are unable to close under supraphysiological pressure gradients.

    “Valve defects lead to increased back leak and an increased ΔP required for closure, even to the point where they are unable to close under supraphysiological pressure gradients (42).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [42]

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Cited by

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Authors
Lapinski, P. E., Lubeck, B. A., Chen, D., Doosti, A., Zawieja, S. D., Davis, M. J., & King, P. D.
Affiliations
  • University of Michigan (US)
  • University of Missouri (US)
Corresponding author
King, Philip D.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2017-05-22
Volume
127
Issue
7
Pages
2569-2585
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci89607
PMC
PMC5490778
OpenAlex
W2616736391
Cited by
71
References
1
Citations by year
2026: 3 · 2025: 9 · 2024: 7 · 2023: 13 · 2022: 7 · 2021: 12 · 2020: 9 · 2019: 3 · 2018: 5 · 2017: 3
FWCI
2.41
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (HL-120888)
  • National Heart, Lung, and Blood Institute (R01HL120867, R01HL120888)
Topics
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Health Sciences › Medicine › Surgery › Vascular Malformations and Hemangiomas
  • Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
Keywords
RASA1, lymphatic endothelial cells, lymphatic leakage, endothelial cell apoptosis
MeSH terms
Animals, Mice, Mutant Strains, Apoptosis, Mutation, Missense, p120 GTPase Activating Protein, Lymphatic Vessels, Endothelial Cells, Mice

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