Advertisement

Journal of Molecular Neuroscience

, Volume 56, Issue 4, pp 898–906 | Cite as

Buyang Huanwu Decoction (BYHWD) Enhances Angiogenic Effect of Mesenchymal Stem Cell by Upregulating VEGF Expression After Focal Cerebral Ischemia

  • Junhong Yang
  • Feng Gao
  • Yunke ZhangEmail author
  • Ying Liu
  • Di Zhang
Article

Abstract

Buyang Huanwu decoction (BYHWD) has been used for centuries to treat paralysis and stroke. Previously, we have demonstrated that BYHWD combined with mesenchymal stem cell (MSC) transplantation attenuates ischemic injury partly by upregulating angiogenesis. However, the mechanisms of this drug for stroke treatment are not completely understood. Here, we aimed to clarify the mechanism of BYHWD on angiogenesis mediated by MSCs. Firstly, we verified microvessels with a size of 50–100 nm produced by either MSCs or MSCs treated by 500 μg/ml BYHWD. These exosomes were purified and found to be able to activate vascular endothelial growth factor (VEGF) expression in endothelial cells (ECs). Moreover, exosomes from MSCs and MSCs treated by BYHWD induced elevated microRNA (miRNA)-126 expression and reduced miR-221 and miR-222 expression. In MSCs, disruption of dicer, an enzyme responsible for miRNA maturation, by dicer small interfering RNA (siRNA), or RNase pretreatment abolished this ability of the exosomes. Additionally, exosomes from MSCs treated by BYHWD promoted VEGF and Ki-67 expression and augmented vascular density in rat brain after bilateral carotid artery ligation. In conclusion, our study revealed that BYHWD exposure augmented angiogenetic miRNA and VEGF expression in exosomes secreted by MSCs and elevated angiogenesis in rat brain.

Keywords

Buyang Huanwu decoction Mesenchymal stem cell Exosome Cerebral ischemia 

Notes

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (NSFC) (No. 81072799)

Conflict of Interest

No conflicts were declared.

Authors’ Contributions

Junhong Yang and Feng Gao contributed to conception and design and acquisition, analysis, and interpretation of data. Ying Liu has been involved in drafting the manuscript or revising it critically for important intellectual content. Yunke Zhang has given final approval of the version to be published. Di Zhang agreed to be accountable for all aspects of the work.

References

  1. Belizon A, Balik E, Feingold DL, Bessler M, Arnell TD, Forde KA, Horst PK, Jain S, Cekic V, Kirman I, Whelan RL (2006) Major abdominal surgery increases plasma levels of vascular endothelial growth factor: open more so than minimally invasive methods. Ann Surg 244:792–798PubMedCentralPubMedCrossRefGoogle Scholar
  2. Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, Morando L, Busca A, Falda M, Bussolati B, Tetta C, Camussi G (2009) Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 20:1053–1067PubMedCentralPubMedCrossRefGoogle Scholar
  3. Cai GX, Liu BY (2010) Effect of ultra-micronized Buyang Huanwu decoction on neurological function, quality of life, and serum vascular endothelial growth factor in patients convalescent from cerebral infarction. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 22:591–594PubMedGoogle Scholar
  4. Chen G, Wu L, Deng CQ (2011) The effects of BuYang HuanWu decoction and its effective components on proliferation-related factors and ERK1/2 signal transduction pathway in cultured vascular smooth muscle cells. J Ethnopharmacol 135:7–14PubMedCrossRefGoogle Scholar
  5. Chen YJ (2009) Effect of Buyang Huanwu decoction on serum vascular endothelial growth factor level of the patients with acute cerebral infarction. J Liaoning Univ Tradit Chin Med 11:113–115Google Scholar
  6. Feigin VL, Lawes CM, Bennett DA, Anderson CS (2003) Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2:43–53PubMedCrossRefGoogle Scholar
  7. Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY, Srivastava D (2008) miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 15:272–284PubMedCentralPubMedCrossRefGoogle Scholar
  8. Hao CZ, Wu F, Shen J, Lu L, Fu DL, Liao WJ, Zheng GQ (2012) Clinical efficacy and safety of Buyang Huanwu decoction for acute ischemic stroke: a systematic review and meta-analysis of 19 randomized controlled trials. Evid Based Complement Alternat Med 630124:21Google Scholar
  9. Huang F, Fang ZF, Hu XQ, Tang L, Zhou SH, Huang JP (2013) Overexpression of miR-126 promotes the differentiation of mesenchymal stem cells toward endothelial cells via activation of PI3K/Akt and MAPK/ERK pathways and release of paracrine factors. Biol Chem 394:1223–1233PubMedGoogle Scholar
  10. Jiang C, Liu P, Zhang J, Bao W, Qiu S, Liang Y, Jiang L (2014) Clinical study of effects of Jian Ji Ning, a Chinese herbal medicine compound preparation, in treating patients with myasthenia gravis via the regulation of differential microRNAs expression in serum. Evid Based Complement Alternat Med 518942:5Google Scholar
  11. Katoh M (2013) Therapeutics targeting angiogenesis: genetics and epigenetics, extracellular miRNAs and signaling networks (review). Int J Mol Med 32:763–767PubMedCentralPubMedGoogle Scholar
  12. Kawabori M, Kuroda S, Ito M, Shichinohe H, Houkin K, Kuge Y, Tamaki N (2013) Timing and cell dose determine therapeutic effects of bone marrow stromal cell transplantation in rat model of cerebral infarct. Neuropathology 33:140–148PubMedCrossRefGoogle Scholar
  13. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4:214–222PubMedCrossRefGoogle Scholar
  14. Lai RC, Tan SS, Teh BJ, Sze SK, Arslan F, de Kleijn DP, Choo A, Lim SK (2012) Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics 971907:18Google Scholar
  15. Lee JK, Park SR, Jung BK, Jeon YK, Lee YS, Kim MK, Kim YG, Jang JY, Kim CW (2013) Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS One 8:e84256PubMedCentralPubMedCrossRefGoogle Scholar
  16. Lin CY, Chang C, Cheung WM, Lin MH, Chen JJ, Hsu CY, Chen JH, Lin TN (2008) Dynamic changes in vascular permeability, cerebral blood volume, vascular density, and size after transient focal cerebral ischemia in rats: evaluation with contrast-enhanced magnetic resonance imaging. J Cereb Blood Flow Metab 28:1491–1501PubMedCrossRefGoogle Scholar
  17. Liu X, Cheng Y, Chen X, Yang J, Xu L, Zhang C (2011) MicroRNA-31 regulated by the extracellular regulated kinase is involved in vascular smooth muscle cell growth via large tumor suppressor homolog 2. J Biol Chem 286:42371–42380PubMedCentralPubMedCrossRefGoogle Scholar
  18. Miyamoto M, Kuroda S, Zhao S, Magota K, Shichinohe H, Houkin K, Kuge Y, Tamaki N (2013) Bone marrow stromal cell transplantation enhances recovery of local glucose metabolism after cerebral infarction in rats: a serial 18F-FDG PET study. J Nucl Med 54:145–150PubMedCrossRefGoogle Scholar
  19. Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, Mercatanti A, Hammond S, Rainaldi G (2006) MicroRNAs modulate the angiogenic properties of HUVECs. Blood 108:3068–3071PubMedCrossRefGoogle Scholar
  20. Ragusa M, Statello L, Maugeri M, Majorana A, Barbagallo D, Salito L, Sammito M, Santonocito M, Angelica R, Cavallaro A, Scalia M, Caltabiano R, Privitera G, Biondi A, Di Vita M, Cappellani A, Vasquez E, Lanzafame S, Tendi E, Celeste S, Di Pietro C, Basile F, Purrello M (2012) Specific alterations of the microRNA transcriptome and global network structure in colorectal cancer after treatment with MAPK/ERK inhibitors. J Mol Med 90:1421–1438PubMedCrossRefGoogle Scholar
  21. Saito H, Magota K, Zhao S, Kubo N, Kuge Y, Shichinohe H, Houkin K, Tamaki N, Kuroda S (2013) 123I-iomazenil single photon emission computed tomography visualizes recovery of neuronal integrity by bone marrow stromal cell therapy in rat infarct brain. Stroke 44:2869–2874PubMedCrossRefGoogle Scholar
  22. Shen LH, Li Y, Chen J, Zhang J, Vanguri P, Borneman J, Chopp M (2006) Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke. Neuroscience 137:393–399PubMedCrossRefGoogle Scholar
  23. Shen LH, Ye M, Ding XS, Han Q, Zhang C, Liu XF, Huang H, Wu EB, Huang HF, Gu XS (2012) Protective effects of MCI-186 on transplantation of bone marrow stromal cells in rat ischemic stroke model. Neuroscience 223:315–324PubMedCrossRefGoogle Scholar
  24. Sheng YH, Jin RM, Yao GT, Zhou L, Qiao JY (2013) Study on early change features of microRNA in the peripheral blood of Sophorae Tonkinensis Radix et Rhizoma induced liver injury rats. Zhongguo Zhong Xi Yi Jie He Za Zhi 33:385–391PubMedGoogle Scholar
  25. Song KH, Kim YH, Kim BY (2014) Sho-saiko-to, a traditional herbal medicine, regulates gene expression and biological function by way of microRNAs in primary mouse hepatocytes. BMC Complement Altern Med 14:1472–6882Google Scholar
  26. Taylor DD, Gercel-Taylor C (2011) Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol 33:441–454PubMedCrossRefGoogle Scholar
  27. Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579PubMedGoogle Scholar
  28. Wang HW, Liou KT, Wang YH, Lu CK, Lin YL, Lee IJ, Huang ST, Tsai YH, Cheng YC, Lin HJ, Shen YC (2011) Deciphering the neuroprotective mechanisms of Bu-yang Huan-wu decoction by an integrative neurofunctional and genomic approach in ischemic stroke mice. J Ethnopharmacol 138:22–33PubMedCrossRefGoogle Scholar
  29. Wang JY, Gao YB, Zhang N, Zou DW, Xu LP, Zhu ZY, Li JY, Zhou SN, Cui FQ, Zeng XJ, Geng JG, Yang JK (2014) Tongxinluo ameliorates renal structure and function by regulating miR-21-induced epithelial-to-mesenchymal transition in diabetic nephropathy. Am J Physiol Ren Physiol 306:26CrossRefGoogle Scholar
  30. Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R, Olson EN (2008) The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell 15:261–271PubMedCentralPubMedCrossRefGoogle Scholar
  31. Wang S, Olson EN (2009) AngiomiRs—key regulators of angiogenesis. Curr Opin Genet Dev 19:205–211PubMedCentralPubMedCrossRefGoogle Scholar
  32. Wei RL, Teng HJ, Yin B, Xu Y, Du Y, He FP, Chu KT, Luo BY, Zheng GQ (2013) A systematic review and meta-analysis of Buyang Huanwu decoction in animal model of focal cerebral ischemia. Evid Based Complement Alternat Med 138484:4Google Scholar
  33. Wei SY, Zhang PX, Yang DM, Zhang HB, Jiang BG (2008) Traditional Chinese medicine and formulas of improving peripheral nerve regeneration. Zhongguo Zhong Yao Za Zhi 33:2069–2072PubMedGoogle Scholar
  34. Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M (2012) Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 30:1556–1564PubMedCentralPubMedCrossRefGoogle Scholar
  35. Xu JN, Que HF, Tang HJ (2009) Effects and action mechanisms of Buyang Huanwu decoction in wound healing of chronic skin ulcers of rats. Zhong Xi Yi Jie He Xue Bao 7:1145–1149PubMedCrossRefGoogle Scholar
  36. Zhang Q, Zhao YH (2014) Therapeutic angiogenesis after ischemic stroke: Chinese medicines, bone marrow stromal cells (BMSCs) and their combinational treatment. Am J Chin Med 42:61–77PubMedCrossRefGoogle Scholar
  37. Zhang YK, Han XY, Che ZY (2010) Effects of Buyang Huanwu tang combined with bone marrow mesenchymal stem cell transplantation on the expression of VEGF and Ki-67 in the brain tissue of the cerebral ischemia-reperfusion model rat. J Tradit Chin Med 30:278–282PubMedCrossRefGoogle Scholar
  38. Zhao HL, Sui Y, Qiao CF, Yip KY, Leung RK, Tsui SK, Lee HM, Wong HK, Zhu X, Siu JJ, He L, Guan J, Liu LZ, Xu HX, Tong PC, Chan JC (2012a) Sustained antidiabetic effects of a berberine-containing Chinese herbal medicine through regulation of hepatic gene expression. Diabetes 61:933–943PubMedCentralPubMedCrossRefGoogle Scholar
  39. Zhao LD, Wang JH, Jin GR, Zhao Y, Zhang HJ (2012b) Neuroprotective effect of Buyang Huanwu decoction against focal cerebral ischemia/reperfusion injury in rats—time window and mechanism. J Ethnopharmacol 140:339–344PubMedCrossRefGoogle Scholar
  40. Zhong W, Peng J, He H, Wu D, Han Z, Bi X, Dai Q (2008) Ki-67 and PCNA expression in prostate cancer and benign prostatic hyperplasia. Clin Invest Med 31:E8–E15PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Junhong Yang
    • 1
  • Feng Gao
    • 2
  • Yunke Zhang
    • 3
    Email author
  • Ying Liu
    • 4
  • Di Zhang
    • 5
  1. 1.The First Department of EncephalopathyThe First Affiliated Hospital of Henan University of Traditional Chinese MedicineZhengzhouChina
  2. 2.Department of Neuroimmunology, Henan Province Academy of Medical and PharmaceuticalZhengzhou UniversityZhengzhouChina
  3. 3.The Second Affiliated Hospital of Henan University of Traditional Chinese MedicineZhengzhouChina
  4. 4.Department of RehabilitationZhengzhou Hospital of Traditional Chinese MedicineZhengzhouChina
  5. 5.Luoyang Center HospitalLuoyangChina

Personalised recommendations