Delineating the role of ERK5 signaling in lymphatic development and homeostasis

Abstract

The lymphatic system has important roles on tissue homeostasis, lipid absorption and immune reaction, and is closely associated with tumor metastasis. Dysregulation of lymphatic system leads to accumulation of lymph fluid and predisposes development of the pathological condition known as lymphedema. While over 100 million people are affected by lymphedema worldwide, only limited therapeutic options are available. Although VEGF-C, which is the ligand of VEGFR3, were considered as a therapeutic candidate, there are some limitation to develop for the therapeutic drug due to their binding affinity to other receptor. To find a proper therapeutic target for lymphatic disease, it is important to understand the molecular mechanism of lymphatic development. Recently, genes that regulate lymphatic development in the presence or absence of VEGF-C / VEGFR3 have been studied, and mechanical forces such as shear stress and cellular stretch, have been reported to activate lymphatic development. ERK5, known as stress-induced protein, has been shown to serve an important regulator for the integrity of blood vessels in response to environmental changes, in particular, shear stress. However, its role in lymphatic vessels remains largely unknown. We find that ERK5 activity in LECs is strongly induced by osmotic stress, but not by flow-induced shear stress. ERK5 in LECs in turn regulates the intracellular function of MEF2C, resulting downregulation of KLF4 transcription. Considering fluid exchange in the capillary bed of our body, lymphatic vessels are exposed to interstitial fluid, which is including high concentration of solute. To verify relationship between ERK5 activation and lymphatic system, we investigate the effect of ERK5 during lymphangiogenesis. First, using erk5-/- zebrafish, we observed that lack of ERK5 activity in zebrafish causes severe edema and decreases the length of the thoracic duct, indicating that ERK5 is essential for lymphatic development. In addition, inhibition of ERK5 activity during tumor formation results in decrease lymphatic vessels coverage in tumor. Taken together, our data indicate that ERK5 activity in response to osmotic stress alters MEF2C transcriptional activity. In addition, altered MEF2C transcriptional activity leads to regulation of KLF2 and KLF4 expression. Therefore, we proposed in this thesis that ERK5 activation in response to osmotic stress is important to develop lymphatic vessels though interstitial fluid, and ERK5 mediated signaling pathway may be a therapeutic target for lymphatic disease, in particular with patients having the interstitial fluid absorbance disorder.