Mechanisms of angiogenesis in a Curculigoside A-treated rat model of cerebral ischemia and reperfusion injury.
Curculigoside A has shown protective effects against rat cortical neuron damage in vivo. However, the molecular mechanisms through which Curculigoside A affords this protection are unclear. In the present study, we sought to elucidate the mechanisms of angiogenesis in rat aortic endothelial cells (RAEC), rat aortic smooth muscle cells (RASMC) as well as a rat model of cerebral ischemia and reperfusion injury following treatment with Curculigoside A. We examined the role of Curculigoside A on RAEC and RASMC proliferation, migration, and tube formation in vitro and in a cerebral ischemia and reperfusion injury rat model. We used the recombinant Dickkopf (DKK)-1 protein, a Wnt/β-catenin inhibitor, and the recombinant WIF-1 protein, a Wnt5a antagonist to determine mechanisms. In addition, we measured leakage of the blood-brain barrier (BBB) and tested for angiogenesis associated proteins. Our data suggest that Curculigoside A induces angiogenesis in vitro by increasing proliferation, migration and tube formation in RAEC and RASMC. The increase in Curculigoside A-induced proliferation and tube formation was counteracted by DKK-1 and WIF-1. Curculigoside A increased expression of VEGF, p-VEGFR, p-CREB, Egr-3, VCAM-1, Ang1 and Tie2 while prohibiting BBB leakage in cerebral ischemia and reperfusion injured rats. However, Cyclosporine A, a CREB inhibitor, reduced the expression of p-CREB, Egr-3, VCAM-1, Ang1 and Tie2. These data suggest that Curculigoside A induces cell proliferation and angiogenesis through the Wnt5a/β-catenin and VEGF/CREB/Egr-3/VCAM-1 signaling axis and promotes maturation and stability of new blood vessels via increasing Ang1 and Tie-2 expression.
School of Public Health and Management, Binzhou Medical University, Yantai, PR China; Institute of Toxicology, Binzhou Medical University, Yantai, PR China.
Haibo
H
Zhu
State Key Laboratory of Long-acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai 264003, PR China.
Jie
J
He
School of Public Health and Management, Binzhou Medical University, Yantai, PR China; Institute of Toxicology, Binzhou Medical University, Yantai, PR China.
Liang
L
Ye
State Key Laboratory of Long-acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai 264003, PR China.
Fei
F
Lin
State Key Laboratory of Long-acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai 264003, PR China.
Jian
J
Hou
State Key Laboratory of Long-acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai 264003, PR China.
Yan
Y
Zhong
School of Pharmaceutical Sciences, Institute of Materia Medica, Binzhou Medical University, Yantai, PR China. Electronic address: jwl518@163.com.
Wanglin
W
Jiang
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D051776:Early Growth Response Protein 3 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy*; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D001565:Benzoates; C531384:Dkk1 protein, rat; C497370:Egr3 protein, rat; D016326:Extracellular Matrix Proteins; D005960:Glucosides; D036341:Intercellular Signaling Peptides and Proteins; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C521045:Wif1 protein, rat; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C491837:Wnt5a protein, rat; D051176:beta Catenin; C467498:vascular endothelial growth factor A, rat; D051776:Early Growth Response Protein 3; C477170:curculigoside; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D040262:Receptors, Vascular Endothelial Growth Factor
Angiogenesis; Blood–brain barrier; Cerebral ischemia; Curculigoside A; Vascular endothelial growth factor; Wnt5a/β-catenin