Abstract
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.