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Functional interaction between CTGF and FPRL1 regulates VEGF-A-induced angiogenesis.

Cellular signalling (2015-04-12)
Mi-Sook Lee, Jaewang Ghim, Sun-Jin Kim, Young Sung Yun, Seung-Ah Yoo, Pann-Ghill Suh, Wan-Uk Kim, Sung Ho Ryu
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.

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Sigma-Aldrich
Phospho(enol)pyruvic acid trisodium salt hydrate, ≥97% (enzymatic)
Sigma-Aldrich
CTGF human, recombinant, expressed in E. coli, ≥95% (SDS-PAGE), ≥95% (HPLC)
Sigma-Aldrich
MISSION® esiRNA, targeting human FPR2