RASA1 regulates the function of lymphatic vessel valves in mice

Lapinski, Philip E.; Lubeck, Beth A.; Chen, Di; Doosti, Abbas; Zawieja, Scott D.; Davis, Michael J.; King, Philip D.

doi:10.1172/jci89607

Cited by 55 publications

(96 citation statements)

References 39 publications

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“…Rasa1 fl/fl and Rasa1 fl/R780Q mice with and without Ub ert2cre transgenes have been described. [16][17][18]20 Cdh5 ert2cre mice were obtained from Cancer Research UK. 29 Immunohistochemistry on sections was performed as described.…”

Section: Methodsmentioning

confidence: 99%

“…18 This can be explained on the basis that RASA1 is required for the maintenance of intra-luminal valves in collecting LV that normally prevent backflow of lymph fluid. 20 Upon Rasa1 disruption, lymphatic EC (LEC) are lost from LV valve leaflets at the rate of approximately one LEC per leaflet per week until a threshold point is reached where the valve is unable to prevent fluid backflow and is unable to function. 20 RASA1 is also necessary for the development of LV valves in late gestation.…”

Section: Introductionmentioning

confidence: 99%

“…20 Upon Rasa1 disruption, lymphatic EC (LEC) are lost from LV valve leaflets at the rate of approximately one LEC per leaflet per week until a threshold point is reached where the valve is unable to prevent fluid backflow and is unable to function. 20 RASA1 is also necessary for the development of LV valves in late gestation. Disruption of Rasa1 just prior to LV valvulogenesis at E15.5 does not impact upon initial LV valve specification characterized by increased expression of the PROX1 transcription factor in valve-forming LEC.…”

Section: Introductionmentioning

confidence: 99%

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RASA1-driven cellular export of collagen IV is required for the development of lymphovenous and venous valves in mice

Chen

Geng

Lapinski

et al. 2020

Preprint

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RASA1, a negative regulator of the Ras-mitogen-activated protein kinase (MAPK) signaling pathway, is essential for the development and maintenance of lymphatic vessel (LV) valves. However, whether RASA1 is required for the development and maintenance of lymphovenous valves (LVV) and venous valves (VV) is unknown. In this study we show that induced endothelial cell (EC)-specific disruption of Rasa1 in mid-gestation mouse embryos did not affect initial specification of LVV or central VV but did affect their continued development. Similarly, switch to expression of a catalytically inactive form of RASA1 resulted in impaired LVV and VV development. Blocked development of LVV in RASA1-deficient embryos was associated with accumulation of the basement membrane protein, collagen IV, in LVV-forming EC and could be partially or completely rescued by MAPK inhibitors and drugs that promote collagen IV folding. Disruption of Rasa1 in adult mice resulted in venous hypertension and impaired VV function that was associated with loss of EC from VV leaflets. In conclusion, RASA1 functions as a negative regulator of Ras signaling in EC that is necessary for EC export of collagen IV, thus permitting the development of LVV and the development and maintenance of VV.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RASA1-driven cellular export of collagen IV is required for the development of lymphovenous and venous valves in mice

Chen

Geng

Lapinski

et al. 2020

Preprint

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“…Ras GTPase-activating protein ( Rasa1 ) deficient mice display loss of lymphatic valves, hyperplasia, dilation, and leakage of lymphatic vessels and chylothorax. In humans, RASA1 mutations cause capillary malformation-arteriovenous malformation (CM-AVM) (577, 578). Transcription factor T-Box 1 ( Tbx1 ) plays a critical role in lymphatic vessel development and regulates the expression of Vegfr3 by binding to an enhancer element in the Flt4 gene (186).…”

Section: Development Of Lymphatic Vessel Networkmentioning

confidence: 99%

Lymphatic Vessel Network Structure and Physiology

Breslin

Yang

Scallan

et al. 2018

Comprehensive Physiology

264

258

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The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease.

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“…Instead, the mice develop LV hyperplasia and leakage that result in chylous ascites and chylothorax (16). Recently, we demonstrated that RASA1 is essential for the development and maintenance of valves in collecting LVs, which accounts for LV leakage in the absence of RASA1 (17).…”

Section: Introductionmentioning

confidence: 99%

RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development

Chen¹,

Teng²,

North³

et al. 2019

Journal of Clinical Investigation

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Global disruption of Rasa1 during developmental angiogenesis results in hemorrhage, edema, and EC apoptosis. To examine the influence of global RASA1 loss upon developmental angiogenesis, pregnant Rasa1 fl/fl mice carrying Rasa1 fl/fl and Rasa1 fl/fl Ub Ert2Cre embryos at the E12.5-E14.5 stage were administered tamoxifen (TM). We found that administration of TM to Rasa1 fl/fl Ub Ert2Cre embryos at this time point resulted in visible cutaneous hemorrhage and an edematous appearance at E18.5 to E19.5 (Table 1 and Figure 1A). Histological analysis of embryos revealed extravasated erythrocytes in skin associated with damaged cutaneous BVs and a vastly reduced number of cutaneous LVs (Figure 1A). We did not observe the same phenotypes in Rasa1 fl/fl Ub Ert2Cre embryos that were not administered TM (Supplemental Figure 1A). Administration of TM to Rasa1 fl/fl Ub Ert2Cre embryos at E15.5 and later also did not result in hemorrhage or other spontaneous embryonic BV abnormalities, although TM administration at this embryonic stage does result in failed LV valve development, as we reported previously (17). Failed LV valve development in embryos administered TM at E15.5 is explained by apoptosis of LV endothelial cells (LECs) in developing LV valve leaflets (17). Therefore, we asked whether disruption of Rasa1 in Rasa1 fl/fl Ub Ert2Cre embryos before E15.5 induced apoptosis of BV endothelial cells (BECs) and LECs in BV and LV walls. As revealed by immunostaining for activated caspase 3, we identified apoptotic BECs in the vast majority of cutaneous BVs of Rasa1 fl/fl Ub Ert2Cre embryos that were administered TM between E12.5 and E14.5, as determined at E18.5 to

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RASA1 regulates the function of lymphatic vessel valves in mice

Cited by 55 publications

References 39 publications

RASA1-driven cellular export of collagen IV is required for the development of lymphovenous and venous valves in mice

RASA1-driven cellular export of collagen IV is required for the development of lymphovenous and venous valves in mice

Lymphatic Vessel Network Structure and Physiology

RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development

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