Lysophosphatidic acid upregulates vascular endothelial growth factor‐C expression in human endothelial cells and enhances lymphangiogenesis

Abstract

Lysophosphatidic acid (LPA) is a small‐molecular‐weight lipid growth factor which binds to G‐protein‐coupled receptors and activates a variety of physiological functions. Previous studies demonstrated that LPA enhances cell proliferation and migration, activation of proteases, and expression of inflammatory‐related genes in human endothelial cells. Furthermore, LPA regulates expression of angiogenic factors such as VEGF‐A in cancer cells which leads to tumor angiogenesis. These results suggested that LPA is an important regulator of vessel functions; however, the role of LPA on lymphatic vessel formation and lymphangiogenesis has not been studied. VEGF‐C has been shown to regulate the development and growth of the lymphatic system. In this study, we showed that LPA upregulated VEGF‐C mRNA expression in human umbilical vascular endothelial cells and subsequent endothelial cell tube formation in vitro and in vivo. These enhancement effects were LPA1‐ and LPA3‐dependent and required COX‐2, EGFR transactivation and activation of NF‐κB. LPA‐induced endothelial tubes expressed the lymphatic marker, Prox‐1. Our results suggest that LPA regulates lymphangiogenesis through the induction of VEGF‐C expression in endothelial cells. This study provides some basic information that LPA might be a novel target for therapeutics against lymphangiogenesis and tumor metastasis.