Objective Lymphatic vessels collect extravasated fluid and proteins from tissues to blood circulation as well as play an essential role in lipid metabolism by taking up intestinal chylomicrons. Previous studies have shown that impairment of lymphatic vessel function causes lymphedema and fat accumulation, but clear connections between arterial pathologies and lymphatic vessels have not been described. Approach and Results Two transgenic mouse strains with lymphatic insufficiency (sVEGFR3 and Chy) were crossed with atherosclerotic mice (LDLR−/−/ApoB100/100) to study the effects of insufficient lymphatic vessel transport on lipoprotein metabolism and atherosclerosis. Both sVEGFR3 × LDLR−/−/ApoB100/100 mice and Chy × LDLR−/−/ApoB100/100 mice had higher plasma cholesterol levels compared to LDLR−/−/ApoB100/100 control mice during both normal chow diet (16.3 mmol/l and 13.7 mmol/l vs. 8.2 mmol/l, respectively) and Western-type high fat diet (e.g. after 2 weeks of fat diet 45.9 mmol/l and 42.6 mmol/l vs. 30.2 mmol/l, respectively). Cholesterol and triglyceride levels in very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) fractions were increased. Atherosclerotic lesions in young and intermediate cohorts of sVEGFR3 × LDLR−/−/ApoB100/100 mice progressed faster than in control mice (e.g. intermediate cohort mice at 6 weeks 18.3% vs. 7.7% of the whole aorta, respectively). In addition, lesions in sVEGFR3 × LDLR−/−/ApoB100/100 mice and Chy × LDLR−/−/ApoB100/100 mice had much less lymphatic vessels than lesions in control mice (0.33% and 1.07% vs. 7.45% of podoplanin positive vessels, respectively). Conclusions We show a novel finding linking impaired lymphatic vessels to lipoprotein metabolism, increased plasma cholesterol levels and enhanced atherogenesis.

Heart has a wide lymphatic network but the importance of cardiac lymphatic system in heart diseases has remained unclear. Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) is a key molecule in the development and maintenance of cardiac lymphatic vessels. Here we characterized the role of VEGFR3 in healthy hearts and after myocardial infarction (MI) by using sVEGFR3 transgenic mice expressing a soluble decoy VEGFR3 under K14 promoter and Chy mice which have an inactivating mutation in the VEGFR3 gene. Cardiac lymphatic vessels were significantly dilated in the healthy hearts of sVEGFR3 mice when compared to controls. Lymphatic vessels formed large sheet-like structures in Chy mice. Attenuated VEGFR3 signaling led to a more severe MI predisposing to a significantly higher mortality in sVEGFR3 mice than in control mice. sVEGFR3 mice displayed intramyocardial hemorrhages in the infarcted area indicating hyperpermeability of the vasculature. Furthermore, novel MRI methods TRAFF2 and TRAFF4 and histological analysis revealed a modified structure of the fibrotic infarcted area in sVEGFR3 mice. In conclusion, the downregulation of VEGFR3 signaling modifies the structure of cardiac lymphatic network and causes vascular leakiness and increased mortality after MI.

Recent progress in lymphatic vessel biology and in novel imaging techniques has established the importance of the lymphatic vasculature as part of the cardiovascular system. The lymphatic vessel network regulates many physiological processes important for heart function such as fluid balance, transport of extravasated proteins, and trafficking of immune cells. Therefore, lymphangiogenic therapy could be beneficial in the treatment of cardiovascular diseases, for example by improving reverse cholesterol transport (RCT) from atherosclerotic lesions or by resolving edema and fibrosis after myocardial infarction. In this review we first describe recent findings on the development and function of cardiac lymphatic vessels, and subsequently focus on the prospects of pro- and anti-lymphangiogenic therapies in cardiovascular diseases.