title: Functional interaction between CTGF and FPRL1 regulates VEGF-A-induced angiogenesis.
abstract: Vascular endothelial growth factor-A (VEGF-A) is a master regulator of angiogenesis that controls several angiogenic processes in endothelial cells. However, the detailed mechanisms of VEGF-A responsible for pleiotropic functions and crosstalk with other signaling pathways have not been fully understood. Here, we found that VEGF-A utilizes the connective tissue growth factor (CTGF)/formyl peptide receptor-like 1 (FPRL1) axis as one of its mediators in angiogenesis. Using a proteomic approach, we found increased secretion of a matricellular protein, CTGF, from VEGF-A-treated human umbilical vein endothelial cells (HUVECs). Then, we studied the effect of CTGF binding to FPRL1 in VEGF-A-induced angiogenesis. CTGF directly binds to FPRL1 through a linker region and activates the downstream signals of FPRL1, such as increase in extracellular signal-regulated kinase (ERK) phosphorylation and intracellular Ca(2+) concentration. We found that linker region-induced FPRL1 activation promotes the migration and network formation of HUVECs, while disruption of FPRL1 inhibits VEGF-A-induced HUVEC migration and network formation. In addition, similar results were observed by the chorioallantoic membrane (CAM) assay based evaluation of angiogenesis in vivo. To summarize, our data reveal a novel working model for VEGF-A-induced angiogenesis via the VEGF-A/CTGF/FPRL1 axis that might prolong and enhance the signals initiated from VEGF-A.
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors: Mi-Sook
authors: MS
authors: Lee
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors: Jaewang
authors: J
authors: Ghim
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors: Sun-Jin
authors: SJ
authors: Kim
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors: Young Sung
authors: YS
authors: Yun
authors: POSTECH-CATHOLIC BioMedical Engineering Institute, The Catholic University of Korea, Seoul 137-701, South Korea.
authors: Seung-Ah
authors: SA
authors: Yoo
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.
authors: Pann-Ghill
authors: PG
authors: Suh
authors: Department of Internal Medicine, Division of Rheumatology, The Catholic University of Korea, Seoul 137-701, South Korea.
authors: Wan-Uk
authors: WU
authors: Kim
authors: Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea. Electronic address: sungho@postech.ac.kr.
authors: Sung Ho
authors: SH
authors: Ryu
mesh_terms: D000595:Amino Acid Sequence; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: C105101:FPR2 protein, human; D034741:RNA, Small Interfering; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D055513:Connective Tissue Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Connective tissue growth factor; Formyl peptide receptor-like 1; Vascular endothelial growth factor-A; WRW4