VEGFC/VEGFR3 Signaling-Dependent Lymphatic Remodeling Modulates Cardiac Response to Pressure Overload
Lina Su1, Yuxia Cui1, Manyan Wu1
1Department of Cardiology, Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Center for Cardiovascular Translational Research Peking University People's Hospital Beijing China.
Insights
Targeting cardiac lymphangiogenesis with vascular endothelial growth factor C (VEGFC) shows promise for heart failure treatment. Enhancing VEGFC/VEGFR3 signaling promotes lymphatic remodeling and reduces inflammation, offering a potential noninvasive therapy.
Area of Science:
- Cardiovascular Biology
- Lymphatic System Research
- Molecular Medicine
Background:
- Cardiac lymphangiogenesis is a potential therapeutic target for heart failure.
- Systemic vascular endothelial growth factor C (VEGFC) delivery shows inconsistent results in promoting cardiac lymphangiogenesis.
- Mechanisms of lymphatic remodeling in heart failure are not well understood.
Purpose of the Study:
- To investigate the role of lymphatic remodeling in heart failure.
- To determine the efficacy of modulating VEGFC/VEGFR3 signaling in heart failure.
- To elucidate the role of Yes-associated protein in VEGFC/VEGFR3 signaling.
Main Methods:
- Adeno-associated virus (AAV)-mediated gene therapy in mice subjected to transverse aortic constriction (TAC).
- AAV-sh-VEGFR3 to inhibit vascular endothelial growth factor receptor 3 (VEGFR3) expression.
- AAV-VEGFC to enhance VEGFC expression.
- In vitro studies on lymphatic endothelial cells.
Main Results:
- TAC induced adaptive cardiac lymphangiogenesis and enhanced peripheral lymphatic transport.
- Inhibition of VEGFR3 exacerbated cardiac inflammation and adverse remodeling.
- VEGFC therapy was cardioprotective, promoting lymphangiogenesis and resolving inflammation.
- VEGFC treatment improved lymphatic drainage and reduced peripheral congestion.
- Yes-associated protein dephosphorylation is crucial for VEGFC/VEGFR3 signaling.
Conclusions:
- Targeting cardiac lymphangiogenesis via VEGFC/VEGFR3 signaling is a promising therapeutic strategy for heart failure.
- VEGFC administration may serve as a noninvasive decongestive approach in heart failure management.
- Modulating the lymphatic system offers a novel therapeutic avenue for heart failure.
Background:
Cardiac lymphangiogenesis has been proposed as a potential therapeutic target to prevent the development of heart failure. However, the efficiency of systemically delivered VEGFC (vascular endothelial growth factor C) protein in inducing cardiac lymphangiogenesis has shown inconsistency across different studies. Moreover, the mechanisms underlying lymphatic remodeling during heart failure remain poorly understood.
Methods:
To determine the role of lymphatic remodeling in heart failure, we used adeno-associated virus-mediated gene therapy to either inhibit VEGFR3 (vascular endothelial growth factor receptor 3) expression or enhance VEGFC expression in mice subjected to transverse aortic constriction. In vitro studies were further conducted to investigate the role of Yes-associated protein in VEGFC/VEGFR3 signaling in lymphatic endothelial cells.
Results:
Our study shows that transverse aortic constriction induces dynamic lymphatic remodeling, characterized by an early adaptive cardiac lymphangiogenic response and enhanced peripheral lymphatic transport function. Adeno-associated virus-sh-VEGFR3 treatment inhibited this early adaptive lymphangiogenesis, exacerbating cardiac inflammation and adverse remodeling. Conversely, adeno-associated virus-VEGFC therapy appeared to be cardioprotective by promoting adaptive lymphangiogenesis and facilitating the resolution of cardiac inflammation. Moreover, adeno-associated virus-VEGFC treatment improved peripheral lymphatic drainage function, potentially alleviating peripheral congestion in heart failure. Further in vivo and in vitro analyses revealed that Yes-associated protein dephosphorylation is essential for VEGFC/VEGFR3 signaling-dependent lymphangiogenesis and for upregulation of lymphatic chemokines and scavenger receptors.
Conclusions:
These findings highlight that targeting cardiac lymphangiogenesis via VEGFC/VEGFR3 signaling through genetic approaches represents a promising therapeutic strategy for heart failure. Moreover, VEGFC administration may offer a novel, noninvasive decongestive approach by modulating the lymphatic system in heart failure management.
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