Abstract 1304: Induction of pericyte migration by autotaxin in angiogenesis

Abstract

Abstract Angiogenesis is essential for tumor cell growth and progression. Recent studies have shown that autotaxin (ATX) is a critical angiogenic factor since ATX knock-out mice exhibit severe vascular defects. ATX also has the ability to stimulate tumor cell motility by enzymatically generating lysophosphatidic acid (LPA). To form a new and stable blood vessel, interactions between pericytes and endothelial cells play important roles. A previous study has shown that endothelial cells can be induced to generate ATX; however little is known about how ATX and LPA are involved in these interactions. The focus of our study is to define the role of ATX in angiogenesis by examining pericyte and endothelial cell response to ATX. To test the effects on cell migration, we treated pericytes and endothelial cells with ATX and other angiogenic factors (including Vascular Endothelial Growth Factor (VEGF) and Platelet Derived Growth Factor (PDGF)). Pericytes responded strongly to ATX and LPA stimulation, but human umbilical vein endothelial cells (HUVEC) and skin microvescular cells (HDMEC) showed little or no effect. PDGF elicits a qualitatively similar response. In contrast, endothelial cells migrated when treated with VEGF, but pericytes showed no such stimulation. Pericytes treated with ATX and PDGF together show an additive response. Moreover, in a checkerboard assay the migratory response to ATX or LPA is chemokinetic, whereas PDGF is chemotactic. We then utilized RT-PCR to examine the mRNA levels of four major LPA receptors in pericytes when treated with angiogenic factors. Treatment with PDGF increases LPAR1 mRNA levels and decreases LPAR4 levels. Treatment with ATX also increases LPAR1, but shows no change in LPAR4 levels. By contrast, VEGF treatment has no effect on the LPAR1 mRNA level, but increases the LPAR4 mRNA level. The amount of migration appears to correlate with an increase of LPAR1 and perhaps a decrease of LPAR4. As such, certain angiogenic factors might affect cell motility, in part, through the differential expression of various LPA receptors. These studies suggest that the ATX/LPA signaling pathway effects the formation of mature blood vessels by promoting the pericyte coverage of immature blood vessels. The role of the ATX/LPA pathway in the formation of mature blood vessels provides the scientific rationale for targeting the pathway in the development of novel anti-angiogenic compounds. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1304.