title: PTEN overexpression attenuates angiogenic processes of endothelial cells by blockade of endothelin-1/endothelin B receptor signaling.
abstract: Arteriovenous (AV) graft is frequently used as vascular access in hemodialysis patients. However, clotting or thrombosis of AV grafts often occurs and requires surgical removal. At present, the molecular pathogenesis underlying thrombosis of AV graft is not clear. The PTEN/Akt signaling has been implicated in the pathogenesis of vascular diseases. In this study, elevated PTEN expression and concomitant Akt inactivation was observed in endothelium of atherosclerotic brachial arteries from hemodialysis patients. To investigate whether PTEN upregulation affects endothelial function, adenovirus-mediated PTEN (Ad-PTEN) overexpression was performed in aorta rings and cultured endothelial cells. It was found that PTEN overexpression potently inhibited the microvessel sprouting in aorta rings and the angiogenic activities of endothelial cells including migration and tube formation. On the contrary, PTEN knockdown by RNA interference promoted the endothelial migration and reversed the Ad-PTEN-induced inhibition of endothelial migration. Expression analysis showed that PTEN overexpression attenuated the expression of endothelin-1 (ET-1) and endothelin B receptor (ETBR) in endothelial cells at transcriptional levels. However, exogenous ET-1 supply only partially reversed the PTEN-induced inhibition of migration and tube formation. This was delineated due to that PTEN overexpression also perturbed endothelial nitric oxide synthase (eNOS) activation and vascular endothelial growth factor (VEGF) release. In summary, PTEN upregulation induces endothelial dysfunction by attenuating the availability and signaling of multiple angiogenic pathways in endothelial cells, thereby may contribute to thrombosis of AV graft.
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, 70 Lien-Hai Rd, Kaohsiung 804, Taiwan.
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Kuo
authors.forename: Chun-Yao
authors.initials: CY
authors.lastname: Lin
authors.forename: Hing-Chung
authors.initials: HC
authors.lastname: Lam
authors.forename: Pey-Ru
authors.initials: PR
authors.lastname: Lin
authors.forename: Hoi-Hung
authors.initials: HH
authors.lastname: Chan
authors.forename: Jui-Cheng
authors.initials: JC
authors.lastname: Tseng
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.forename: Te-Fa
authors.initials: TF
authors.lastname: Hsu
authors.forename: Chia-Ching
authors.initials: CC
authors.lastname: Wu
authors.forename: Chao-Yuh
authors.initials: CY
authors.lastname: Yang
authors.forename: Ching-Mei
authors.initials: CM
authors.lastname: Hsu
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Tai
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D002465:Cell Movement; D042783:Endothelial Cells / Q000201:enzymology*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006083:Graft Occlusion, Vascular / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology; D006801:Humans; D008297:Male; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism*; D006435:Renal Dialysis; D015398:Signal Transduction; D013927:Thrombosis / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D046509:Tissue Culture Techniques; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D044023:Receptor, Endothelin B; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human