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JAHA 2018.pdf (4.15 MB)

JAHA 2018.pdf

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journal contribution
posted on 2019-03-05, 03:02 authored by Yuuki Shimizu, Rohini Polavarapu, Kattri-Liis Eskla, Yvanna Pantner, Chad Nicholson, Masakazu Ishii, Daniel Brunnhoelzl, Rohit Mauria, Ahsan Husain, Nawazish Naqvi, Toyoaki Murohara, John Calvert

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.


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