Journal Article

Zoledronate Attenuates Angiogenic Effects of Angiotensin II-Stimulated Endothelial Progenitor Cells via RhoA and MAPK Signaling

Chen, Fei, Chen, Bin, Han, Jie, Yang, Jin-Xiu, Pan, Yan-Yun, Hu, Shen-Jiang

2012

Overview

New vessel formation plays a pivotal role in the pathogenesis of neovascular-related diseases. Endothelial progenitor cells (EPCs) were found to contribute to neovascular-related diseases and interference with EPC neovascularization may be a novel target for these diseases. Zoledronate (Zol) was reported to exhibit anti-angiogenic effect. Basing on these evidences, we proposed that Zol may affect EPC function to exert novel anti-angiogenic effect. In this study, we therefore investigated the effects of Zol on multiple aspects of EPC function and explored the underlying mechanisms involved. EPCs were cultured from bone marrow derived mononuclear cells. The potential effects of Zol on Angiotensin II (Ang II)-stimulated EPC proliferation, migration, adhesion, in vitro tube formation were investigated. The results showed that Ang II (1 µM) enhanced EPC migration, adhesion, in vitro tube formation but had no effect on cell proliferation. Zol (75 and 100 µM) inhibited proliferation of EPCs and 50 µM geranylgeranyol (GGOH) could reverse the decrease of EPC proliferation. We found for the first time that Zol (50-100 µM) dose dependently attenuated migration, adhesion, and in vitro tube formation of EPCs stimulated by Ang II. GGOH could reverse the attenuation of EPC function induced by Zol. However, Zol did not induce EPC apoptosis. In addition, the underlying mechanisms were determined. The results revealed that Zol markedly down-regulated active RhoA stimulated by Ang II and inhibited the phosphorylation of Erk1/2 and JNK. Moreover, RhoA silencing resulted in a notable inhibition of EPC in vitro tube formation, suggesting that RhoA suppression played a pivotal role in Zol antiangiogenic effect. These findings suggested that Zol attenuated the promotion of EPC function stimulated by Ang II and exhibited novel antiangiogenic effect via RhoA and MAPK signaling. Thus, Zol may be served as a novel therapeutic agent for neovascular-related diseases treatment.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adhesion / Analysis / Angiogenesis / Angiotensin / Angiotensin II / Angiotensin II - pharmacology / Angiotensins / Animals / Antiangiogenics / Apoptosis / Atherosclerosis / Attenuation / Base Sequence / Biology / Blotting, Western / Bone marrow / Cancer / Cardiology / Cell growth / Cell proliferation / Cells (biology) / Cells, Cultured / Chemical compounds / Diabetic retinopathy / Diphosphonates - pharmacology / Diseases / DNA Primers / Dosage and administration / Endothelium, Vascular - cytology / Endothelium, Vascular - drug effects / Flow Cytometry / Health aspects / Imidazoles - pharmacology / JNK protein / Kinases / Leukocytes (mononuclear) / Male / MAP kinase / MAP Kinase Signaling System / Medical treatment / Medicine / Microscopy / Mitogen-activated protein kinases / Neovascularization / Neovascularization, Physiologic - drug effects / Pathogenesis / Pharmacology / Phosphorylation / Physiological aspects / Proteins / Rats / Rats, Sprague-Dawley / rhoA GTP-Binding Protein - metabolism / RhoA protein / Rodents / Signal Transduction - drug effects / Signaling / Stem cells / Stem Cells - cytology / Stem Cells - drug effects / Vascular endothelial growth factor / Vascularization / Zoledronate / Zoledronic acid