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Updated: Jan 30, 2026
Author Spotlight: Exploring the Relationship Between Lipotoxicity and HFpEF
Published on: March 29, 2024
Therapeutic Lymphangiogenesis Using Induced Cardiac Fibroblasts Protects the Heart From Heart Failure With Preserved
Haihang Luo1, Yuuki Shimizu1, Takahiro Iwamiya2
1Department of Cardiology, Nagoya University Graduate School of Medicine.
Insights
Therapeutic lymphangiogenesis, promoting new lymphatic vessel growth, shows promise for treating heart failure with preserved ejection fraction (HFpEF). This approach targets cardiac lymphatic dysfunction, a key factor in HFpEF progression.
Area of Science:
- Cardiovascular Research
- Lymphatic Biology
- Translational Medicine
Background:
- Heart failure with preserved ejection fraction (HFpEF) presents a significant global health challenge with limited treatment options.
- The underlying mechanisms of HFpEF development and progression are not fully understood.
- Emerging evidence highlights the critical role of cardiac lymphatic vessels in cardiovascular health.
Purpose of the Study:
- To investigate the dynamics and function of cardiac lymphatic vessels in a mouse model of HFpEF.
- To explore the therapeutic potential of stimulating lymphatic vessel formation (lymphangiogenesis) for HFpEF treatment.
Main Methods:
- Utilized a two-hit HFpEF mouse model (high-fat diet + L-NAME).
- Observed cardiac lymphatic vessel kinetics and characterized VCAM1-positive cardiac fibroblasts (VCFs).
- Conducted cellular experiments involving lymphatic endothelial cells and assessed therapeutic lymphangiogenesis via VCF implantation.
Main Results:
- Cardiac lymphatic rarefaction correlated with HFpEF progression.
- Inhibition of lymphangiogenesis exacerbated cardiac remodeling and dysfunction.
- VCAM1-positive cardiac fibroblasts promoted lymphatic vessel formation, partly via VEGF-C/VEGFR3 signaling.
- Therapeutic lymphangiogenesis using VCF implantation improved cardiac remodeling and function in the HFpEF model.
Conclusions:
- Cardiac lymphatic vessels are integral to HFpEF progression and cardiac function.
- Stimulating lymphangiogenesis represents a novel therapeutic strategy for managing HFpEF.
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.
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