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.