Impact of Lymphangiogenesis on Cardiac Remodeling After Ischemia and Reperfusion Injury

Abstract

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 (C57 BL /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.

Human cardiac fibroblasts expressing VCAM1 improve heart function in postinfarct heart failure rat models by stimulating lymphangiogenesis

“…Cardiac lymphangiogenesis plays a central role in maintaining fluid homeostasis for healthy heart contraction [18]. Recent studies have suggested that lymphangiogenesis improves cardiac function and healing by draining accumulated fluids and maintaining the physiological interstitial fluid equilibrium [19,20,70]. These studies, together with our RNA sequencing data, suggested that VCFs have a favorable expression of genes related to the regulation of blood and/or lymph vessel formation.…”

“…Additionally, numerous studies have reported that cardiac lymphatic vessels play a key role in maintaining fluid homeostasis, which is critical for healthy heart contraction [18]. Recently, targeting cardiac lymphatic vasculature is thought to provide a therapeutic benefit to heart function after myocardial infarction [19,20]. Thus, we hypothesized that VCFs might have the potential to improve cardiac function in heart failure by triggering angiogenesis and/or lymphangiogenesis.…”

“…Additionally, the PDGF/PDGFR axis is known as an important regulator of blood vessel development and lymphangiogenesis [44,45]. VEGF-C has been identified as a key molecule in cardiac angiogenesis and lymphangiogenesis through the activation of the VEGFC/VEGFR-3 pathway, leading to the improvement of cardiac function after myocardial infarction [19,20,47]. Conversely, VNCFs express genes promoting cardiac remodeling.…”

“…Moreover, the mechanisms of lymphatic endothelial cell-fibroblast signaling have not yet been elucidated. As mentioned above, VEGFC, which is listed in S2 Table as a gene upregulated in VCFs, is involved in cardiac lymphangiogenesis through the activation of the VEGFC/ VEGFR-3 pathway leading to the improvement of cardiac function after myocardial infarction [19,20,47]. However, it is unclear whether VCFs have the potential to improve the signal transduction of the VEGFC/VEGFR-3 axis; therefore, rapamycin (therapeutically available as sirolimus)-treated rats should be investigated to confirm the involvement of the signaling pathways.…”

Granulomatous Inflammation in Tuberculosis and Sarcoidosis: Does the Lymphatic System Contribute to Disease?

“…In contrast to the detrimental relationship between lymphangiogenesis in cancer, an expanded lymphatic network during infection facilitates immune cell trafficking to infected tissues and helps mobilize the associated increase in interstitial fluid. In this way, lymphangiogenesis also contributes to tissue regeneration, leading to improved outcomes following wound and ischemic injury events …”