Skip to main content
SpringerLink
Log in

AAMP Regulates Endothelial Cell Migration and Angiogenesis Through RhoA/Rho Kinase Signaling

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

An Erratum to this article was published on 29 December 2015

Abstract

Angiogenesis is a complicated process including endothelial cell proliferation, migration and tube formation. AAMP plays a role in regulating cell migration of multiple cell types. The purpose of this study was to investigate whether AAMP regulates angiogenesis, and to clarify the role of AAMP in the VEGF-induced angiogenesis. We found that AAMP expressed in multiple cell types and mainly localized in cytoplasm and membrane in vascular endothelial cells. Using tube formation assay in vitro and aortic ring assay, siRNA-mediated knockdown and antibody blockade of AAMP impaired VEGF-induced endothelial cell tube formation and aortic ring angiogenic sprouting. Mechanistic studies showed that AAMP expression was significantly upregulated by VEGF in a concentration and time-dependent manner. Moreover, VEGF recruited AAMP to the cell membrane protrusions. AAMP regulates angiogenesis by mediating the spreading and migration of vascular endothelial cells. AAMP knock-down reduced VEGF-induced actin stress fibers and collagen gel contraction. Furthermore, we identified RhoA/Rho kinase signaling as an important factor that contributes to the action of AAMP in regulating endothelial cell migration and angiogenesis. Altogether, these data demonstrated the critical role of AAMP in angiogenesis and suggested blocking AAMP could serve as a potential therapeutic strategy for angiogenesis-related diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Adeyinka, A., E. Emberley, Y. Niu, L. Snell, L. C. Murphy, H. Sowter, C. C. Wykoff, A. L. Harris, and P. R. H. Watson. Analysis of gene expression in ductal carcinoma in situ of the breast. Clin. Cancer Res. 8:3788–3795, 2002.

    CAS  PubMed  Google Scholar 

  2. Allander, S. V., N. N. Nupponen, M. Ringnér, G. Hostetter, G. W. Maher, N. Goldberger, Y. Chen, J. Carpten, A. G. Elkahloun, and P. S. Meltzer. Gastrointestinal stromal tumors with KIT mutations exhibit a remarkably homogeneous gene expression profile. Cancer Res. 61:8624–8628, 2001.

    CAS  PubMed  Google Scholar 

  3. Baker, M., S. D. Robinson, T. Lechertier, P. R. Barber, B. Tavora, G. D’Amico, D. T. Jones, B. Vojnovic, and K. Hodivala-Dilke. Use of the mouse aortic ring assay to study angiogenesis. Nat. Protoc. 7(1):89–104, 2012.

    Article  CAS  Google Scholar 

  4. Beckner, M. E., H. C. Krutzsch, M. L. Stracke, S. T. Williams, J. A. Gallardo, and L. A. Liotta. Identification of a new immunoglobulin superfamily protein expressed in blood vessels with a heparin-binding consensus sequence. Cancer Res. 55:2140–2149, 1995.

    CAS  PubMed  Google Scholar 

  5. Beckner, M. E., and L. A. Liotta. AAMP, a conserved protein with immunoglobulin and WD40 domains, regulates endothelial tube formation in vitro. Lab. Invest. 75:97–107, 1996.

    CAS  PubMed  Google Scholar 

  6. Beckner, M. E., V. A. Peterson, and D. E. Moul. Angio-associated migratory cell protein is expressed as an extracellular protein by blood-vessel-associated mesenchymal cells. Microvasc. Res. 57:347–352, 1999.

    Article  CAS  PubMed  Google Scholar 

  7. Beckner, M. E., S. Jagannathan, and V. A. Peterson. Extracellular angio-associated migratory cell protein plays a positive role in angiogenesis and is regulated by astrocytes in coculture. Microvasc. Res. 63:259–269, 2002.

    Article  CAS  PubMed  Google Scholar 

  8. Bielig, H., B. Zurek, A. Kutsch, M. Menning, D. J. Philpott, P. J. Sansonetti, and T. A. Kufer. A function for AAMP in Nod2-mediated NF-kappaB activation. Mol. Immunol. 46(13):2647–2654, 2009.

    Article  CAS  PubMed  Google Scholar 

  9. Birk, D. M., J. Barbato, L. Mureebe and R.A. Chaer. Current insights on the biology and clinical aspects of VEGF regulation. Vasc. Endovascular. Surg. 42(6):517-530, 2008-2009.

  10. Blanchoin, L., R. Boujemaa-Paterski, C. Sykes, and J. Plastino. Actin dynamics, architecture, and mechanics in cell motility. Physiol. Rev. 94(1):235–263, 2014.

    Article  CAS  PubMed  Google Scholar 

  11. Blanco, R., and H. Gerhardt. VEGF and Notch in tip and stalk cell selection. Cold Spring Harb. Perspect. Med. 3(1):a006569, 2013.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Bryan, B. A., E. Dennstedt, D. C. Mitchell, T. E. Walshe, K. Noma, R. Loureiro, M. Saint-Geniez, J. P. Campaigniac, J. K. Liao, and P. A. D’Amore. RhoA/ROCK signaling is essential for multiple aspects of VEGF-mediated angiogenesis. FASEB J. 24(9):3186–3195, 2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Carmeliet, P., and R. K. Jain. Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307, 2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen, W., K. Mao, Z. Liu, and A. T. Dinh-Xuan. The role of the RhoA/Rho kinase pathway in angiogenesis and its potential value in prostate cancer. Oncol. Lett. 8(5):1907–1911, 2014.

    PubMed  PubMed Central  Google Scholar 

  15. Chi, Q., T. Yin, H. Gregersen, X. Deng, Y. Fan, J. Zhao, D. Liao, and G. Wang. Rear actomyosin contractility-driven directional cell migration in three-dimensional matrices: a mechano-chemical coupling mechanism. J. R. Soc. Interface 11(95):20131072, 2014.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ferrara, N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am. J. Physiol. Cell Physiol. 280(6):C1358–C1366, 2001.

    CAS  PubMed  Google Scholar 

  17. Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1(1):27–31, 1995.

    Article  CAS  PubMed  Google Scholar 

  18. Fong, G. H., J. Rossant, M. Gertsenstein, and M. L. Breitman. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376:66–70, 1995.

    Article  CAS  PubMed  Google Scholar 

  19. Frelin, C., A. Ladoux, and G. D’angelo. Vascular endothelial growth factors and angiogenesis. Ann. Endocrinol (Paris) 61:70–74, 2000.

    CAS  Google Scholar 

  20. Hoang, M. V., M. C. Whelan, and D. R. Senger. Rho activity critically and selectively regulates endothelial cell organization during angiogenesis. Proc. Natl. Acad. Sci. USA 101(7):1874–1879, 2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Holvoet, P., and P. Sinnaeve. Angio-associated migratory cell protein and smooth muscle cell migration in development of restenosis and atherosclerosis. J. Am. Coll. Cardiol. 52:312–314, 2008.

    Article  CAS  PubMed  Google Scholar 

  22. Lamalice, L., F. Le Boeuf, and J. Huot. Endothelial cell migration during angiogenesis. Circ. Res. 100(6):782–794, 2007.

    Article  CAS  PubMed  Google Scholar 

  23. Liekens, S., E. De Clercq, and J. Neyts. Angiogenesis: regulators and clinical applications. Biochem. Pharmacol. 61:253–270, 2001.

    Article  CAS  PubMed  Google Scholar 

  24. Machacek, M., L. Hodgson, C. Welch, H. Elliott, O. Pertz, P. Nalbant, A. Abell, G. L. Johnson, K. M. Hahn, and G. Danuser. Coordination of Rho GTPase activities during cell protrusion. Nature 461(7260):99–103, 2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ngo, P., P. Ramalingam, J. A. Phillips, and G. T. Furuta. Collagen gel contraction assay. Methods Mol. Biol. 341:103–109, 2006.

    CAS  PubMed  Google Scholar 

  26. Pertz, O., L. Hodgson, R. L. Klemke, and K. M. Hahn. Spatiotemporal dynamics of RhoA activity in migrating cells. Nature 440(7087):1069–1072, 2006.

    Article  CAS  PubMed  Google Scholar 

  27. Phng, L. K., F. Stanchi, and H. Gerhardt. Filopodia are dispensable for endothelial tip cell guidance. Development 140(19):4031–4040, 2013.

    Article  CAS  PubMed  Google Scholar 

  28. Potente, M., H. Gerhardt, and P. Carmeliet. Basic and therapeutic aspects of angiogenesis. Cell 146(6):873–887, 2011.

    Article  CAS  PubMed  Google Scholar 

  29. Qiu, J., G. Wang, Y. Zheng, J. Hu, Q. Peng, and T. Yin. Coordination of Id1 and p53 activation by oxidized LDL regulates endothelial cell proliferation and migration. Ann. Biomed. Eng. 39(12):2869–2878, 2011.

    Article  PubMed  Google Scholar 

  30. Qiu, J., G. Wang, Q. Peng, J. Hu, X. Luo, Y. Zheng, Y. Teng, and C. Tang. Id1 induces tubulogenesis by regulating endothelial cell adhesion and cytoskeletal organization through β1-integrin and Rho-kinase signalling. Int. J. Mol. Med. 28(4):543–548, 2011.

    CAS  PubMed  Google Scholar 

  31. Qiu, J., Q. Peng, Y. Zheng, J. Hu, X. Luo, Y. Teng, T. Jiang, T. Yin, C. Tang, and G. Wang. OxLDL stimulates Id1 nucleocytoplasmic shuttling in endothelial cell angiogenesis via PI3 K pathway. Biochim. Biophys. Acta. 1821(10):1361–1369, 2012.

    Article  CAS  PubMed  Google Scholar 

  32. Reid, H. M., K. Wikström, D. J. Kavanagh, E. P. Mulvaney, and B. T. Kinsella. Interaction of angio-associated migratory cell protein with the TPα and TPβ isoforms of the human thromboxane A2 receptor. Cell Signal 23(4):700–717, 2011.

    Article  CAS  PubMed  Google Scholar 

  33. Reymann, A. C., R. Boujemaa-Paterski, J. L. Martiel, C. Guérin, W. Cao, H. F. Chin, E. M. De La Cruz, M. Théry, and L. Blanchoin. Actin network architecture can determine myosin motor activity. Science 336(6086):1310–1314, 2012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sakakura, K., M. Nakano, F. Otsuka, E. Ladich, F. D. Kolodgie, and R. Virmani. Pathophysiology of atherosclerosis plaque progression. Heart Lung Circ. 22(6):399–411, 2013.

    Article  PubMed  Google Scholar 

  35. Sharghi-Namini, S., E. Tan, L. L. Ong, R. Ge, and H. H. Asada. Dll4-containing exosomes induce capillary sprout retraction in a 3D microenvironment. Sci. Rep. 4:4031, 2014.

    Article  PubMed  PubMed Central  Google Scholar 

  36. van Nieuw Amerongen, G. P., M. A. Vermeer, P. Nègre-Aminou, J. Lankelma, J. J. Emeis, and V. W. van Hinsbergh. Simvastatin improves disturbed endothelial barrier function. Circulation 102(23):2803–2809, 2000.

    Article  PubMed  Google Scholar 

  37. van Nieuw Amerongen, G. P., P. Koolwijk, A. Versteilen, and V. W. van Hinsbergh. Involvement of RhoA/Rho kinase signaling in VEGF-induced endothelial cell migraton and angiogenesis in vitro. Arterioscler. Thromb. Vasc. Biol. 23(2):211–217, 2003.

    Article  PubMed  Google Scholar 

  38. Vogt, F., A. Zernecke, M. Beckner, N. Krott, A. K. Bosserhoff, R. Hoffmann, M. A. Zandvoort, T. Jahnke, M. Kelm, C. Weber, and R. Blindt. Blockade of angio-associated migratory cell protein inhibits smooth muscle cell migration and neointima formation in accelerated atherosclerosis. J. Am. Coll. Cardiol. 52:302–311, 2008.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This study was supported by grants from the National Natural Science Foundation of China (31370949, 11332003, 81400329), the Fundamental Research Funds for the Central Universities (CQDXWL-2012-120), Chongqing Science and Technology Commission (cstc2013kjrc-ljrccj10003) and we also thanks for the support from the Chongqing Engineering Laboratory in Vascular Implants,the National “111 Plan” Base (B06023) and the Public Experiment Center of State Bioindustrial Base (Chongqing), China.

Author information

Authors and Affiliations

  1. Key Laboratory for Biorheological Science and Technology of Ministry of Education (Chongqing University), State and Local Joint Engineering Laboratory For Vascular Implants (Chongqing), Bioengineering College of Chongqing University, Chongqing, 400030, China

    Jianjun Hu, Juhui Qiu, Yiming Zheng, Tao Zhang, Tieying Yin, Xiang Xie & Guixue Wang

Authors
  1. Jianjun Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juhui Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yiming Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tieying Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiang Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guixue Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guixue Wang.

Additional information

Associate Editor Michael Gower oversaw the review of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 530 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, J., Qiu, J., Zheng, Y. et al. AAMP Regulates Endothelial Cell Migration and Angiogenesis Through RhoA/Rho Kinase Signaling. Ann Biomed Eng 44, 1462–1474 (2016). https://doi.org/10.1007/s10439-015-1442-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-015-1442-0

Keywords

Search

Navigation