[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Simultaneous measurement of RBC velocity, flux, hematocrit and shear rate in vascular networks

Nature Methods volume 7, pages 655–660 (2010)Cite this article

Subjects

Abstract

Not all tumor vessels are equal. Tumor-associated vasculature includes immature vessels, regressing vessels, transport vessels undergoing arteriogenesis and peritumor vessels influenced by tumor growth factors. Current techniques for analyzing tumor blood flow do not discriminate between vessel subtypes and only measure average changes from a population of dissimilar vessels. We developed methodologies for simultaneously quantifying blood flow (velocity, flux, hematocrit and shear rate) in extended networks at single-capillary resolution in vivo. Our approach relies on deconvolution of signals produced by labeled red blood cells as they move relative to the scanning laser of a confocal or multiphoton microscope and provides fully resolved three-dimensional flow profiles within vessel networks. Using this methodology, we show that blood velocity profiles are asymmetric near intussusceptive tissue structures in tumors in mice. Furthermore, we show that subpopulations of vessels, classified by functional parameters, exist in and around a tumor and in normal brain tissue.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Description, validation and application of RTLS and RVFS.
Figure 2: Analysis of cross-sectional flow profiles in tumor vessels undergoing intussusceptive angiogenesis.
Figure 3: Multiparametric phenotypic vessel clustering to compare vessels in tumor, peritumor and contralateral brain regions in a glioma model.

Similar content being viewed by others

References

  1. Fukumura, D., Yuan, F., Monsky, W.L., Chen, Y. & Jain, R.K. Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. Am. J. Pathol. 151, 679–688 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Brizel, D.M. et al. A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model. Int. J. Radiat. Oncol. Biol. Phys. 25, 269–276 (1993).

    Article  CAS  Google Scholar 

  3. Endrich, B., Reinhold, H.S., Gross, J.F. & Intaglietta, M. Tissue perfusion inhomogeneity during early tumor growth in rats. J. Natl. Cancer Inst. 62, 387–395 (1979).

    CAS  PubMed  Google Scholar 

  4. Nagy, J.A., Chang, S.H., Dvorak, A.M. & Dvorak, H.F. Why are tumour blood vessels abnormal and why is it important to know? Br. J. Cancer 100, 865–869 (2009).

    Article  CAS  Google Scholar 

  5. Kamoun, W.S., Schmugge, S.J., Kraftchick, J.P., Clemens, M.G. & Shin, M.C. Liver microcirculation analysis by red blood cell motion modeling in intravital microscopy images. IEEE Trans. Biomed. Eng. 55, 162–170 (2008).

    Article  Google Scholar 

  6. Rosenblum, W.I. & El-Sabban, F. Measurement of red cell velocity with a two-slit technique and cross-correlation: use of reflected light, and either regulated dc or unregulated ac power supplies. Microvasc. Res. 22, 225–227 (1981).

    Article  CAS  Google Scholar 

  7. Kleinfeld, D., Mitra, P.P., Helmchen, F. & Denk, W. Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex. Proc. Natl. Acad. Sci. USA 95, 15741–15746 (1998).

    Article  CAS  Google Scholar 

  8. Brown, E.B. et al. In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy. Nat. Med. 7, 864–868 (2001).

    Article  CAS  Google Scholar 

  9. Drew, P.J., Blinder, P., Cauwenberghs, G., Shih, A.Y. & Kleinfeld, D. Rapid determination of particle velocity from space-time images using the Radon transform. J. Comput. Neurosci. published online, doi:10.1007/s10827-009-0159-1 (21 May 2009).

  10. Lindsey, E.S., Donaldson, G.W. & Woodruff, M.F. Erythrocyte survival in normal mice and in mice with autoimmune haemolytic anaemia. Clin. Exp. Immunol. 1, 85–98 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Patan, S. et al. Vascular morphogenesis and remodeling in a human tumor xenograft: blood vessel formation and growth after ovariectomy and tumor implantation. Circ. Res. 89, 732–739 (2001).

    Article  CAS  Google Scholar 

  12. Jain, R.K., Tong, R.T. & Munn, L.L. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res. 67, 2729–2735 (2007).

    Article  CAS  Google Scholar 

  13. Frangos, J.A., McIntire, L.V. & Eskin, S.G. Shear stress induced stimulation of mammalian cell metabolism. Biotechnol. Bioeng. 32, 1053–1060 (1988).

    Article  CAS  Google Scholar 

  14. Jain, R.K., Munn, L.L. & Fukumura, D. Dissecting tumour pathophysiology using intravital microscopy. Nat. Rev. Cancer 2, 266–276 (2002).

    Article  CAS  Google Scholar 

  15. Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553–563 (2004).

    CAS  Google Scholar 

  16. Tyrrell, J.A. et al. Robust 3-D modeling of vasculature imagery using superellipsoids. IEEE Trans. Med. Imaging 26, 223–237 (2007).

    Article  Google Scholar 

Download references

Acknowledgements

We thank T. Padera for editorial comments and S. Roberge for technical assistance. This work was supported in part by US National Institutes of Health grants R01HL064240 (L.L.M.), R01CA149285 (L.L.M.) and P01CA80124 (R.K.J.) and by a postdoctoral fellowship from the Susan G. Komen Foundation (W.S.K.).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Walid S Kamoun, Sung-Suk Chae, Delphine A Lacorre, Mariela Mitre, Marijn A Gillissen, Dai Fukumura, Rakesh K Jain & Lance L Munn

  2. Thomson Reuters, Corporate Research & Development, New York, New York, USA

    James A Tyrrell

Authors
  1. Walid S Kamoun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sung-Suk Chae
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Delphine A Lacorre
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James A Tyrrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mariela Mitre
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marijn A Gillissen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dai Fukumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rakesh K Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lance L Munn
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.S.K. conceived and designed the experiment, validated and implemented the technique, collected data and wrote the manuscript. S.-S.C., D.A.L. and M.A.G. implemented the technique and collected data. J.A.T. conceived and designed the experiment and validated the technique. M.M. validated the technique. D.F. conceived and designed the experiment and provided administrative support. R.K.J. provided administrative and financial support and edited the manuscript. L.L.M. conceived and designed the experiment, provided administrative and financial support and wrote the manuscript.

Corresponding author

Correspondence to Lance L Munn.

Ethics declarations

Competing interests

R.K.J. has advisory roles at AstraZeneca, Dyax, Enlight, SynDevRx, Millennium (1 time), Genzyme (1 time), Morphosys (1 time), Astellas (1 time) and Regeneron (1 time), and received honoraria for giving a lecture at Pfizer and Genzyme.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 2438 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kamoun, W., Chae, SS., Lacorre, D. et al. Simultaneous measurement of RBC velocity, flux, hematocrit and shear rate in vascular networks. Nat Methods 7, 655–660 (2010). https://doi.org/10.1038/nmeth.1475

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nmeth.1475

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer