title: Pristimerin inhibits angiogenesis in adjuvant-induced arthritic rats by suppressing VEGFR2 signaling pathways.
abstract: Rheumatoid arthritis (RA) is a progressive, inflammatory autoimmune disease. As RA progresses, the hyperplastic synovial pannus creates a hypoxic, inflammatory environment that induces angiogenesis. Further vascularization of the synovial tissue promotes pannus growth and continued infiltration of inflammatory leukocytes, thus perpetuating the disease. Pristimerin inhibits inflammation and tumor angiogenesis. The present study focused on the inhibition of angiogenesis by Pristimerin in adjuvant-induced arthritic rats and the underlying molecular mechanisms. Our results clearly demonstrate for the first time that Pristimerin significantly reduces vessel density in synovial membrane tissues of inflamed joints and reduces the expression of pro-angiogenic factors in sera, including TNF-α, Ang-1, and MMP-9. Pristimerin also decreased the expression of VEGF and p-VEGFR2 in the synovial membrane, whereas the total amount of VEGFR2 remained unchanged. Pristimerin suppressed the sprouting vessels of the aortic ring and inhibited VEGF-induced HFLS-RA migration in vitro. Pristimerin also inhibited VEGF-induced proliferation, migration and tube formation by HUVECs, blocked the autophosphorylation of VEGF-induced VEGFR2 and consequently downregulated the signaling pathways of activated PI3K, AKT, mTOR, ERK1/2, JNK, and p38 in VEGF-induced HUVECs. Our results indicate that Pristimerin suppressed synovial angiogenesis in our rat model and in vitro by interrupting the targeting of VEGFR2 activation. Therefore, Pristimerin has potential as an angiogenesis inhibitor in the treatment of rheumatoid arthritis.
authors.affiliation: School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Qiudi
authors.initials: Q
authors.lastname: Deng
authors.affiliation: School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Shutong
authors.initials: S
authors.lastname: Bai
authors.affiliation: School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Wanjiao
authors.initials: W
authors.lastname: Gao
authors.affiliation: School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China. Electronic address: TongliSMU@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Tong
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D053978:Pentacyclic Triterpenes; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013583:Synovial Membrane / Q000473:pathology; D014315:Triterpenes / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D042683:Angiopoietin-1; D061965:Matrix Metalloproteinase Inhibitors; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; C000602029:Kdr protein, rat; D040301:Vascular Endothelial Growth Factor Receptor-2; D020780:Matrix Metalloproteinase 9; C050414:celastrol
keywords: Angiogenesis; Pristimerin; Rheumatoid arthritis