Therapeutic Lymphangiogenesis Using Induced Cardiac Fibroblasts Protects the Heart From Heart Failure With Preserved Ejection Fraction Progression by Exerting Anti-Inflammatory and Antifibrotic Effects

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is an unmet clinical need and a serious problem worldwide because of the limited therapeutic options. Moreover, the precise mechanisms of its onset or progression remain unknown. The important role of cardiac lymphatic vessels has recently received attention, so we investigated the kinetics and role of cardiac lymphatic vessels in the setting of HFpEF and tested the therapeutic potential for therapeutic lymphangiogenesis against HFpEF. METHODS AND RESULTS: We observed the kinetics of cardiac lymphatic vessels in HFpEF induced by a 2-hit model (with a high-fat diet [HFD]+L-NAME) in wild-type mice. Cardiac lymphatic rarefaction was observed in a series of HFpEF progression. Additionally, we verified that inhibition of lymphangiogenesis aggravates cardiac remodeling and dysfunction in the HFpEF model. VCAM1-positive cardiac fibroblasts (VCFs) augmented lymphatic vessel formation and progression in the heart and the lymphangiogenic effect of VCFs were partly mediated by VEGF-C-VEGFR3 signaling, based on cellular experiments using lymphatic endothelial cells. We verified that therapeutic lymphangiogenesis with VCF implantation could ameliorate cardiac remodeling and dysfunction in HFpEF. CONCLUSIONS: Cardiac lymphatic vessels play an important role in remodeling and function in HFpEF progression. Moreover, lymphangiogenesis could be a novel therapeutic target for HFpEF.