Abstract 16221: Therapeutic Lymphangiogenesis Ameliorates Cardiac Dysfunction in the Setting of Ischemic-induced Heart Failure
Background: Lymphatic vessels exist throughout the body in the same manner as blood vessels. They interconnect with blood vessels to form an elaborate system that function in interstitial fluid drainage, lipid absorption, and immune cell responses. Although the lymphatic system has been known to exist in a heart, very little is known about its role in either physiological or pathological conditions. Here we sought to determine if modulation of lymphangiogenesis following ischemic injury has beneficial effect on the development of heart failure.
Methods and Results: Initial studies revealed that lymphatic vessels are uniformly distributed in the heart like blood vessels, but exist at a density one-tenth that of blood vessels. Next, we examined the density of lymphatic vessels in response to myocardial ischemia. For these studies, mice (C57BL/6J, male, 10 weeks of age) were subjected to permanent left coronary artery occlusion. After 14 days, we observed increased lymphatic vessel density in both the border and infarct area. Analysis of heart sections also revealed an increase in the expression of VEGF-C and VEGF-A. Interestingly, the localization of both cytokines was distinct with the majority of VEGF-C being localized to the endocardium. Next, we examined the effects of in vivo treatment of VEGF-C. For these studies, mice subjected to permanent MI were given VEGF-C (1.25 μg/mouse) by placing a gelatin hydrogel on the surface of the myocardium. Analysis at 14 days of ischemia revealed that VEGF-C treatment augmented lymphangiogenesis, reduced the size of the infarct scar, and improved left ventricular ejection fraction. Finally, we tested if the augmentation of lymphangiogenesis with VEGF-C would improve cardiac dysfunction after ischemia-reperfusion (I/R) injury. After induction of I/R, mice (N=27) were divided to 4 groups: saline, VEGF-C, MAZ51 (VEGFR3 inhibitor) and VEGF-C+MAZ51 treatment groups and followed for 4 weeks. VEGF-C improved cardiac function, whereas MAZ51 worsened cardiac function.
Conclusions: These results suggest that lymphangiogenesis occurs following the onset of myocardial ischemia and that augmenting lymphangiogenesis with VEGF-C treatment attenuates the development of ischemic heart failure.
Author Disclosures: Y. Shimizu: None. R. Polavarapu: None. T. Murohara: None. J. Calvert: None.
- © 2016 by American Heart Association, Inc.