[HTML][HTML] RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice

PE Lapinski, S Kwon, BA Lubeck… - The Journal of …, 2012 - Am Soc Clin Investig
PE Lapinski, S Kwon, BA Lubeck, JE Wilkinson, RS Srinivasan, E Sevick-Muraca, PD King
The Journal of clinical investigation, 2012Am Soc Clin Investig
RASA1 (also known as p120 RasGAP) is a Ras GTPase–activating protein that functions as
a regulator of blood vessel growth in adult mice and humans. In humans, RASA1 mutations
cause capillary malformation–arteriovenous malformation (CM-AVM); whether it also
functions as a regulator of the lymphatic vasculature is unknown. We investigated this issue
using mice in which Rasa1 could be inducibly deleted by administration of tamoxifen.
Systemic loss of RASA1 resulted in a lymphatic vessel disorder characterized by extensive …
RASA1 (also known as p120 RasGAP) is a Ras GTPase–activating protein that functions as a regulator of blood vessel growth in adult mice and humans. In humans, RASA1 mutations cause capillary malformation–arteriovenous malformation (CM-AVM); whether it also functions as a regulator of the lymphatic vasculature is unknown. We investigated this issue using mice in which Rasa1 could be inducibly deleted by administration of tamoxifen. Systemic loss of RASA1 resulted in a lymphatic vessel disorder characterized by extensive lymphatic vessel hyperplasia and leakage and early lethality caused by chylothorax (lymphatic fluid accumulation in the pleural cavity). Lymphatic vessel hyperplasia was a consequence of increased proliferation of lymphatic endothelial cells (LECs) and was also observed in mice in which induced deletion of Rasa1 was restricted to LECs. RASA1-deficient LECs showed evidence of constitutive activation of Ras in situ. Furthermore, in isolated RASA1-deficient LECs, activation of the Ras signaling pathway was prolonged and cellular proliferation was enhanced after ligand binding to different growth factor receptors, including VEGFR-3. Blockade of VEGFR-3 was sufficient to inhibit the development of lymphatic vessel hyperplasia after loss of RASA1 in vivo. These findings reveal a role for RASA1 as a physiological negative regulator of LEC growth that maintains the lymphatic vasculature in a quiescent functional state through its ability to inhibit Ras signal transduction initiated through LEC-expressed growth factor receptors such as VEGFR-3.
The Journal of Clinical Investigation