Downregulation of VEGFR3 signaling alters cardiac lymphatic vessel organization and leads to a higher mortality after acute myocardial infarction

Abstract

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.

Regulation of Lymphatic Function in Obesity

“…Reports indicate that after an MI incident, there is a profound remodeling of cardiac lymphatic vessels, and that augmentation of this response by VEGF-C treatment can lead to improved cardiac function (Klotz et al, 2015). These findings are also supported by data from soluble VEGFR-3 decoy transgenic mice (sVEGFR-3) and Chy mice, which reveal that downregulation of VEGFR-3 signaling structurally alters the cardiac lymphatic vasculature and increases mortality after MI (Vuorio et al, 2018). In addition to VEGF-C, adrenomedullin, a known cardioprotective peptide, is also shown to induce cardiac lymphatic growth and function after MI (Trincot et al, 2019).…”

The Lymphatic System in Obesity, Insulin Resistance, and Cardiovascular Diseases

“…Improved outcome by VEGFC-induced lymphangiogenesis depends on lymphatic-mediated immune cell clearance through a pathway involving LEC expressed LYVE-1 (Vieira et al, 2018). Consistent with a protective role of the lymphatic vasculature in promoting post-MI recovery, downregulation of the LEC marker VEGFR3 alters cardiac lymphatic structure, increases lymphatic leakage, and raises MI-induced mortality (Vuorio et al, 2018). These recent studies suggest that the lymphatic vasculature might be a viable therapeutic target for post-MI cardiac repair (Vuorio et al, 2017).…”

Angiotensin II Stimulates the Proliferation and Migration of Lymphatic Endothelial Cells Through Angiotensin Type 1 Receptors

“…However, lymphatic dysfunction, either due to gene mutations or secondary to damage to the lymphatic vessels, may lead to lymphedema, chylothorax, inflammation, and tumor metastasis (Aspelund et al, 2016;Hu et al, 2019;Xiao et al, 2019). Interestingly, there are several reports indicating a relationship between cardiac lymphatic dysfunction, edema, and contractile dysfunction in animals with myocardial infarction (MI) or ischemia/reperfusion (I/R) injury (Klotz et al, 2015;Henri et al, 2016;Shimizu et al, 2018;Vuorio et al, 2018). Therefore, it is important to elucidate the regulatory mechanisms underlying lymphatic vessel growth (also known as lymphangiogenesis).…”