VEGF-C/VEGFR-3 axis protects against pressure-overload induced cardiac dysfunction through regulation of lymphangiogenesis.

Abstract

Prolonged pressure overload triggers cardiac hypertrophy and frequently leads to heart failure (HF). Vascular endothelial growth factor‐C (VEGF‐C) and its receptor VEGFR‐3 are components of the central pathway for lymphatic vessel growth (also known as lymphangiogenesis), which has crucial functions in the maintenance of tissue fluid balance and myocardial function after ischemic injury. However, the roles of this pathway in the development of cardiac hypertrophy and dysfunction during pressure overload remain largely unknown. Eight‐ to 10‐week‐old male wild‐type (WT) mice, VEGFR‐3 knockdown (VEGFR‐3f/−) mice, and their WT littermates (VEGFR‐3f/f) were subjected to pressure overload induced by transverse aortic constriction (TAC) for 1–6 weeks. We found that cardiac lymphangiogenesis and the protein expression of VEGF‐C and VEGFR‐3 were upregulated in the early stage of cardiac hypertrophy but were markedly reduced in failing hearts. Moreover, TAC for 6 weeks significantly reduced cardiac lymphangiogenesis by inhibiting activation of VEGFR‐3‐mediated signals (AKT/ERK1/2, calcineurin A/NFATc1/FOXc2, and CX43), leading to increased cardiac edema, hypertrophy, fibrosis, apoptosis, inflammation, and dysfunction. These effects were further aggravated in VEGFR‐3f/− mice and were dose‐dependently attenuated by delivery of recombinant VEGF‐C156S in WT mice. VEGF‐C156s administration also reversed pre‐established cardiac dysfunction induced by sustained pressure overload. Thus, these results demonstrate, for the first time, that activation of the VEGF‐C‐VEGFR‐3 axis exerts a protective effect during the transition from cardiac hypertrophy to HF and highlight selective stimulation of cardiac lymphangiogenesis as a potential new therapeutic approach for hypertrophic heart diseases.