Impact of Lymphangiogenesis on Cardiac Remodeling After Ischemia and Reperfusion Injury

• Type of Material: Article
• Authors: Yuuki Shimizu, Emory University; Rohini Polavarapu, Emory University; Kattri-Liis Eskla, Emory University; Yvanna Pantner, Emory University; Chad K. Nicholson, Emory University; Masakazu Ishii, Nagoya University; Daniel Brunnhoelzl, Emory University; Rohit Mauria, Emory University; Ahsan Husain, Emory University; Nawazish Naqvi, Emory University; Toyoaki Murohara, Nagoya University; John Calvert, Emory University
• Language: English
• Date: 2018-10-02
• Publisher: Wiley Open Access: Creative Commons Attribution Non-Commercial
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1161/JAHA.118.009565
• Title of Journal or Parent Work: Journal of the American Heart Association
• ISSN: 2047-9980
• Volume: 7
• Issue: 19
• Start Page: e009565
• End Page: e009565
• Grant/Funding Information: This work was also supported by funding from the Carlyle Fraser Heart Center of Emory University Hospital Midtown (Calvert).; 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).
• Keywords: GROWTH-FACTOR-C; FLOW; LYMPHATIC VASCULATURE; lymphangiogenesis; Science & Technology; heart failure; Cardiac & Cardiovascular Systems; INDUCED HEART-FAILURE; MECHANISMS; myocardial ischemia; UP-REGULATION; ANGIOGENESIS; Life Sciences & Biomedicine; VEGF; Cardiovascular System & Cardiology; THERAPEUTIC LYMPHANGIOGENESIS; lymphatics; SUPPRESSION
• Research Categories: Health Sciences, General

Abstract

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.