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Metabolic Brain Disease

, Volume 33, Issue 5, pp 1679–1688 | Cite as

PTEN inhibition enhances angiogenesis in an in vitro model of ischemic injury by promoting Akt phosphorylation and subsequent hypoxia inducible factor-1α upregulation

  • Lixia Xue
  • Jiankang Huang
  • Ting Zhang
  • Xiuzhe Wang
  • Jianliang Fu
  • Zhi Geng
  • Yuwu Zhao
  • Hao Chen
Original Article

Abstract

Angiogenesis is an important pathophysiological response to cerebral ischemia. PTEN is a lipid phosphatase whose loss activates PI3K/Akt signaling, which is related to HIF-1α upregulation and enhanced angiogenesis in human cancer cells. However, the specific roles of PTEN in endothelial cell functions and angiogenesis after cerebral ischemia remain unknown. Therefore, we sought to examine the potential effects of PTEN inhibition on post-ischemic angiogenesis in human blood vessel cells and to determine the underlying mechanism. In this present study, human umbilical vein endothelial cells (HUVECs) were exposed to oxygen-glucose deprivation (OGD), cell proliferation, migration and apoptosis, in vitro tube formation and expression of PTEN/Akt pathway and angiogenic factors were examined in HUVECs after treatment with PTEN inhibitor bisperoxovanadium (bpV) at different doses. The results showed that bpV significantly increased the cell proliferation and reduced cell apoptosis indicating that the drug exerts a cytoprotective effect on HUVECs with OGD exposure. bpV also enhanced cell migration and tube formation in HUVECs following OGD, and upregulated HIF-1α and VEGF expressions, but attenuated endostatin expression. Additionally, western blotting analysis demonstrated that Akt phosphorylation in HUVECs was significantly increased after bpV treatment. These findings suggest that PTEN inhibition promotes post-ischemic angiogenesis in HUVECs after exposure to OGD and this enhancing effect might be achieved through activation of the Akt signal cascade.

Keywords

Angiogenesis PTEN Human umbilical vein endothelial cells Oxygen-glucose deprivation Hypoxia inducible factor-1α Akt 

Notes

Acknowledgments

This study was supported by National Natural Science Foundation of China (81501657) and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital Foundation (LYZY-0101).

Compliance with ethical standards

Conflict of interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. Bouvard C, Galy-Fauroux I, Grelac F, Carpentier W, Lokajczyk A, Gandrille S, Colliec-Jouault S, Fischer AM, Helley D (2015) Low-molecular-weight Fucoidan induces endothelial cell migration via the PI3K/AKT pathway and modulates the transcription of genes involved in angiogenesis. Mar Drugs 13:7446–7462CrossRefPubMedPubMedCentralGoogle Scholar
  2. Ci X, Xing C, Zhang B, Zhang Z, Ni JJ, Zhou W, Dong JT (2015) KLF5 inhibits angiogenesis in PTEN-deficient prostate cancer by attenuating AKT activation and subsequent HIF-1α accumulation. Mol Cancer 14:91CrossRefPubMedPubMedCentralGoogle Scholar
  3. Ergul A, Alhusban A, Fagan SC (2012) Angiogenesis: a harmonized target for recovery after stroke. Stroke 43:2270–2274CrossRefPubMedPubMedCentralGoogle Scholar
  4. Greenberg DA, Jin K (2013) Vascular endothelial growth factors (VEGFs) and stroke. Cell Mol Life Sci 70:1753–1761CrossRefPubMedPubMedCentralGoogle Scholar
  5. Guo JY, Ding J, Yuan F, Chen H, Chen SW, Tian HL (2013) Dose-dependent protective effect of bisperoxovanadium against acute cerebral ischemia in a rat model of ischemia/reperfusion injury. Int J Mol Sci 14:12013–12022CrossRefPubMedPubMedCentralGoogle Scholar
  6. Hillion JA, Li Y, Maric D, Takanohashi A, Klimanis D, Barker JL, Hallenbeck JM (2006) Involvement of Akt in preconditioning-induced tolerance to ischemia in PC12 cells. J Cereb Blood Flow Metab 26:1323–1331CrossRefPubMedPubMedCentralGoogle Scholar
  7. Huang JJ, Shi YQ, Li RL, Hu A, Lu ZY, Weng L, Wang SQ, Han YP, Zhang L, Li B, Hao CN, Duan JL (2015) Angiogenesis effect of therapeutic ultrasound on HUVECs through activation of the PI3K-Akt-eNOS signal pathway. Am J Transl Res 7:1106–1115PubMedPubMedCentralGoogle Scholar
  8. Jiang BH, Liu LZ (2009) PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res 02:19–65CrossRefGoogle Scholar
  9. Kar S, Samii A, Bertalanffy H (2015) PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurg Rev 38:229–236CrossRefPubMedGoogle Scholar
  10. Li D, Qu Y, Mao M, Zhang X, Li J, Ferriero D, Mu D (2009) Involvement of the PTEN-AKT-FOXO3a pathway in neuronal apoptosis in developing rat brain after hypoxia-ischemia. J Cereb Blood Flow Metab 29:1903–1913CrossRefPubMedPubMedCentralGoogle Scholar
  11. Li WL, Fraser JL, Yu SP, Zhu J, Jiang YJ, Wei L (2011) The role of VEGF/VEGFR2 signaling in peripheral stimulation-induced cerebral neurovascular regeneration after ischemic stroke in mice. Exp Brain Res 214:503–513CrossRefPubMedGoogle Scholar
  12. Liu J, Wang Y, Akamatsu Y, Lee CC, Stetler RA, Lawton MT, Yang GY (2014) Vascular remodeling after ischemic stroke: mechanisms and therapeutic potentials. Prog Neurobiol 115:138–156CrossRefPubMedGoogle Scholar
  13. Ma Y, Zechariah A, Qu Y, Hermann DM (2012) Effects of vascular endothelial growth factor in ischemic stroke. J Neurosci Res 90:1873–1882CrossRefPubMedGoogle Scholar
  14. Ma F, Morancho A, Montaner J, Rosell A (2015) Endothelial progenitor cells and revascularization following stroke. Brain Res 1623:150–159CrossRefPubMedGoogle Scholar
  15. Mao L, Jia J, Zhou X, Xiao Y, Wang Y, Mao X, Zhen X, Guan Y, Alkayed NJ, Cheng J (2013) Delayed administration of a PTEN inhibitor BPV improves functional recovery after experimental stroke. Neuroscience 231:272–281CrossRefPubMedGoogle Scholar
  16. Mao L, Huang M, Chen SC, Li YN, Xia YP, He QW, Wang MD, Huang Y, Zheng L, Hu B (2014) Endogenous endothelial progenitor cells participate in neovascularization via CXCR4/SDF-1axis and improve outcome after stroke. CNS Neurosci Ther 20:460–468CrossRefPubMedGoogle Scholar
  17. Ponce ML (2009) Tube formation: an in vitro matrigel angiogenesis assay. Methods Mol Biol 467:183–188CrossRefPubMedGoogle Scholar
  18. Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674CrossRefPubMedGoogle Scholar
  19. Serra H, Chivite I, Angulo-Urarte A, Soler A, Sutherland JD, Arruabarrena-Aristorena A, Ragab A, Lim R, Malumbres M, Fruttiger M, Potente M, Serrano M, Fabra À, Viñals F, Casanovas O, Pandolfi PP, Bigas A, Carracedo A, Gerhardt H, Graupera M (2015) PTEN mediates notch-dependent stalk cell arrest in angiogenesis. Nat Commun 6:7935CrossRefPubMedPubMedCentralGoogle Scholar
  20. Shi F, Wang YC, Zhao TZ, Zhang S, Du TY, Yang CB, Li YH, Sun XQ (2012) Effects of simulated microgravity on human umbilical vein endothelial cell angiogenesis and role of the PI3K-Akt-eNOS signal pathway. PLoS One 7:e40365CrossRefPubMedPubMedCentralGoogle Scholar
  21. Sun J, Zhou W, Ma D, Yang Y (2010) Endothelial cells promote neural stem cell proliferation and differentiation associated with VEGF activated notch and Pten signaling. Dev Dyn 239:2345–2353CrossRefPubMedGoogle Scholar
  22. Unseld M, Chilla A, Pausz C, Mawas R, Breuss J, Zielinski C, Schabbauer G, Prager GW (2015) PTEN expression in endothelial cells is down-regulated by uPAR to promote angiogenesis. Thromb Haemost 114:379–389CrossRefPubMedGoogle Scholar
  23. Walia A, Yang JF, Huang YH, Rosenblatt MI, Chang JH, Azar DT (2015) Endostatin's emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications. Biochim Biophys Acta 1850:2422–2438CrossRefPubMedPubMedCentralGoogle Scholar
  24. Xing Y, Lai J, Liu X, Zhang N, Ming J, Liu H, Zhang X (2017) Netrin-1 restores cell injury and impaired angiogenesis in vascular endothelial cells upon high glucose by PI3K/AKT-eNOS. J Mol Endocrinol 58:167–177CrossRefPubMedGoogle Scholar
  25. Xiong T, Tang J, Zhao J, Chen H, Zhao F, Li J, Qu Y, Ferriero D, Mu D (2012) Involvement of the Akt/GSK-3β/CRMP-2 pathway in axonal injury after hypoxic-ischemic brain damage in neonatal rat. Neuroscience 216:123–132CrossRefPubMedGoogle Scholar
  26. Xue L, Chen H, Lu K, Huang J, Duan H, Zhao Y (2017a) Clinical significance of changes in serum neuroglobin and HIF-1α concentrations during the early-phase of acute ischemic stroke. J Neurol Sci 375:52–57CrossRefPubMedGoogle Scholar
  27. Xue L, Chen H, Zhang T, Chen J, Geng Z, Zhao Y (2017b) Changes in serum vascular endothelial growth factor and endostatin concentrations associated with circulating endothelial progenitor cells after acute ischemic stroke. Metab Brain Dis 32:641–648CrossRefPubMedGoogle Scholar
  28. Yang JP, Liu HJ, Liu XF (2010) VEGF promotes angiogenesis and functional recovery in stroke rats. J Investig Surg 23:149–155CrossRefGoogle Scholar
  29. Zechariah A, ElAli A, Doeppner TR, Jin F, Hasan MR, Helfrich I, Mies G, Hermann DM (2013) Vascular endothelial growth factor promotes pericyte coverage of brain capillaries, improves cerebral blood flow during subsequent focal cerebral ischemia, and preserves the metabolic penumbra. Stroke 44:1690–1697CrossRefPubMedGoogle Scholar
  30. Zhao J, Qu Y, Wu J, Cao M, Ferriero DM, Zhang L, Mu D (2013) PTEN inhibition prevents rat cortical neuron injury after hypoxia-ischemia. Neuroscience 238:242–251CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyShanghai Jiao Tong University Affiliated Sixth People′s HospitalShanghaiChina
  2. 2.Department of NeurosurgeryShanghai Jiao Tong University Affiliated Sixth People′s HospitalShanghaiChina

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