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Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract
Peter Baluk1, Li-Chin Yao1, Julio C Flores1
1Cardiovascular Research Institute, Department of Anatomy, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
Abstract:
Lymphatic malformations are serious but poorly understood conditions that present therapeutic challenges. The goal of this study was to compare strategies for inducing regression of abnormal lymphatics and explore underlying mechanisms. CCSP-rtTA/tetO-VEGF-C mice, in which doxycycline regulates VEGF-C expression in the airway epithelium, were used as a model of pulmonary lymphangiectasia. After doxycycline was stopped, VEGF-C expression returned to normal, but lymphangiectasia persisted for at least 9 months. Inhibition of VEGFR-2/VEGFR-3 signaling, Notch, β-adrenergic receptors, or autophagy and antiinflammatory steroids had no noticeable effect on the amount or severity of lymphangiectasia. However, rapamycin inhibition of mTOR reduced lymphangiectasia by 76% within 7 days without affecting normal lymphatics. Efficacy of rapamycin was not increased by coadministration with the other agents. In prevention trials, rapamycin suppressed VEGF-C-driven mTOR phosphorylation and lymphatic endothelial cell sprouting and proliferation. However, in reversal trials, no lymphatic endothelial cell proliferation was present to block in established lymphangiectasia, and rapamycin did not increase caspase-dependent apoptosis. However, rapamycin potently suppressed Prox1 and VEGFR-3. These experiments revealed that lymphangiectasia is remarkably resistant to regression but is responsive to rapamycin, which rapidly reduces and normalizes the abnormal lymphatics without affecting normal lymphatics.
Insights
Rapamycin effectively treats pulmonary lymphangiectasia, a lymphatic malformation, by inhibiting mTOR. This targeted approach rapidly reduces abnormal lymphatics without harming healthy ones, offering a promising therapeutic strategy.
Area of Science:
- Vascular Biology
- Developmental Biology
- Pharmacology
Background:
- Lymphatic malformations, such as pulmonary lymphangiectasia, are poorly understood and pose significant therapeutic challenges.
- Current therapeutic strategies for lymphatic malformations lack efficacy.
Purpose of the Study:
- To compare different therapeutic strategies for inducing regression of abnormal lymphatics.
- To explore the underlying mechanisms of lymphatic malformation regression.
Main Methods:
- Utilized CCSP-rtTA/tetO-VEGF-C mice, a model for pulmonary lymphangiectasia regulated by doxycycline-induced VEGF-C expression.
- Administered various inhibitors targeting VEGFR-2/VEGFR-3 signaling, Notch, β-adrenergic receptors, autophagy, and anti-inflammatory steroids.
- Investigated the effect of rapamycin (mTOR inhibitor) in both prevention and reversal of lymphangiectasia.
- Assessed lymphatic endothelial cell proliferation, apoptosis, Prox1, and VEGFR-3 expression.
Main Results:
- Pulmonary lymphangiectasia persisted for at least 9 months after doxycycline withdrawal, despite normalized VEGF-C levels.
- Inhibition of VEGFR-2/VEGFR-3, Notch, β-adrenergic receptors, autophagy, and steroids showed no significant effect on lymphangiectasia.
- Rapamycin treatment reduced lymphangiectasia by 76% within 7 days without impacting normal lymphatics.
- Rapamycin suppressed VEGF-C-driven mTOR phosphorylation, lymphatic endothelial cell sprouting, and proliferation in prevention trials.
- In established lymphangiectasia, rapamycin reduced Prox1 and VEGFR-3 expression but did not increase apoptosis or block proliferation.
Conclusions:
- Established pulmonary lymphangiectasia is highly resistant to regression via multiple targeted pathways.
- Rapamycin demonstrates potent efficacy in reducing and normalizing abnormal lymphatics, acting independently of lymphatic endothelial cell proliferation.
- Rapamycin represents a promising therapeutic agent for treating lymphatic malformations like pulmonary lymphangiectasia.
