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Author Notes:

Correspondence to: John W. Calvert, PhD, Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, 380 Northyards Blvd, Ste B, Atlanta, GA 30313. E‐mail: jcalver@emory.edu

Disclosures: None.


Research Funding:

This work was funded by grants from the American Heart Association (15POST25610016 to Shimizu, 17GRNT33670975 to Naqvi, and 16GRNT31190016 to Calvert) and the National Institutes of Health (R01DK115213 and R01HL136915 to Calvert).

This work was also supported by funding from the Carlyle Fraser Heart Center of Emory University Hospital Midtown (Calvert).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Cardiac & Cardiovascular Systems
  • Cardiovascular System & Cardiology
  • heart failure
  • lymphangiogenesis
  • lymphatics
  • myocardial ischemia
  • FLOW
  • VEGF

Impact of Lymphangiogenesis on Cardiac Remodeling After Ischemia and Reperfusion Injury

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Journal Title:

Journal of the American Heart Association


Volume 7, Number 19


, Pages e009565-e009565

Type of Work:

Article | Final Publisher PDF


Background Lymphatic vessels interconnect with blood vessels to form an elaborate system that aids in the control of tissue pressure and edema formation. Although the lymphatic system has been known to exist in a heart, little is known about the role the cardiac lymphatic system plays in the development of heart failure. Methods and Results Mice (C57BL/6J, male, 8 to 12 weeks of age) were subjected to either myocardial ischemia or myocardial ischemia and reperfusion for up to 28 days. Analysis revealed that both models increased the protein expression of vascular endothelial growth factor C and VEGF receptor 3 starting at 1 day after the onset of injury, whereas a significant increase in lymphatic vessel density was observed starting at 3 days. Further studies aimed to determine the consequences of inhibiting the endogenous lymphangiogenesis response on the development of heart failure. Using 2 different pharmacological approaches, we found that inhibiting VEGF receptor 3 with MAZ‐51 and blocking endogenous vascular endothelial growth factor C with a neutralizing antibody blunted the increase in lymphatic vessel density, blunted lymphatic transport, increased inflammation, increased edema, and increased cardiac dysfunction. Subsequent studies revealed that augmentation of the endogenous lymphangiogenesis response with vascular endothelial growth factor C treatment reduced inflammation, reduced edema, and improved cardiac dysfunction. Conclusions These results suggest that the endogenous lymphangiogenesis response plays an adaptive role in the development of ischemic‐induced heart failure and supports the emerging concept that therapeutic lymphangiogenesis is a promising new approach for the treatment of cardiovascular disease.

Copyright information:

© 2018 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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