Skip to main content

Advertisement

Log in

Visualizing vascular permeability and lymphatic drainage using labeled serum albumin

  • Original Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

During the early stages of angiogenesis, following stimulation of endothelial cells by vascular endothelial growth factor (VEGF), the vascular wall is breached, allowing high molecular weight proteins to leak from the vessels to the interstitial space. This hallmark of angiogenesis results in deposition of a provisional matrix, elevation of the interstitial pressure and induction of interstitial convection. Albumin, the major plasma protein appears to be an innocent bystander that is significantly affected by these changes, and thus can be used as a biomarker for vascular permeability associated with angiogenesis. Traditionally, albumin leak in superficial organs was followed by colorimetry or morphometry with the use of albumin binding vital dyes. Over the last years, the introduction of tagged-albumin that can be detected by various imaging methods, such as magnetic resonance imaging and positron emission tomography, opened new possibilities for quantitative three dimension dynamic analysis of permeability in any organ. Using these tools it is now possible to follow not only vascular permeability, but also interstitial convection and lymphatic drain. Active uptake of tagged albumin by caveolae-mediated endocytosis opens the possibility for using labeled albumin for vital staining of cells and cell tracking. This approach was used for monitoring recruitment of perivascular stroma fibroblasts associated with tumor angiogenesis.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Leung DW, Cachianes G, Kuang WJ et al (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309

    Article  PubMed  CAS  Google Scholar 

  2. Dvorak HF (2006) Discovery of vascular permeability factor (VPF). Exp Cell Res 312:522–526

    Article  PubMed  CAS  Google Scholar 

  3. Dvorak HF, Nagy JA, Feng D et al (1999) Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr Top Microbiol Immunol 237:97–132

    PubMed  CAS  Google Scholar 

  4. Dvorak AM, Feng D (2001) The vesiculo-vacuolar organelle (VVO). A new endothelial cell permeability organelle. J Histochem Cytochem 49:419–432

    PubMed  CAS  Google Scholar 

  5. Nagy JA, Benjamin L, Zeng H et al (2008) Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 11:109–119

    Article  PubMed  CAS  Google Scholar 

  6. Miles AA, Miles EM (1952) Vascular reactions to histamine, histamine-liberator and leukotaxine in the skin of guinea-pigs. J Physiol 118:228–257

    PubMed  CAS  Google Scholar 

  7. Kratz F (2008) Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release 132:171–183

    Article  PubMed  CAS  Google Scholar 

  8. Hsia JC, Wong LT, Tan CT et al (1984) Bovine serum albumin: characterization of a fatty acid binding site on the N-terminal peptic fragment using a new spin-label. Biochemistry 23:5930–5932

    Article  PubMed  CAS  Google Scholar 

  9. Doweiko JP, Nompleggi DJ (1991) Role of albumin in human physiology and pathophysiology. JPEN J Parenter Enteral Nutr 15:207–211

    Article  PubMed  CAS  Google Scholar 

  10. Schmiedl U, Ogan MD, Moseley ME et al (1986) Comparison of the contrast-enhancing properties of albumin-(Gd-DTPA) and Gd-DTPA at 2.0 T: and experimental study in rats. AJR Am J Roentgenol 147:1263–1270

    PubMed  CAS  Google Scholar 

  11. Pham CD, Roberts TP, van Bruggen N et al (1998) Magnetic resonance imaging detects suppression of tumor vascular permeability after administration of antibody to vascular endothelial growth factor. Cancer Invest 16:225–230

    Article  PubMed  CAS  Google Scholar 

  12. Daldrup H, Shames DM, Wendland M et al (1998) Correlation of dynamic contrast-enhanced magnetic resonance imaging with histologic tumor grade: comparison of macromolecular and small-molecular contrast media. Pediatr Radiol 28:67–78

    Article  PubMed  CAS  Google Scholar 

  13. Ogan MD, Schmiedl U, Moseley ME et al (1987) Albumin labeled with Gd-DTPA. An intravascular contrast-enhancing agent for magnetic resonance blood pool imaging: preparation and characterization. Invest Radiol 22:665–671

    Article  PubMed  CAS  Google Scholar 

  14. Yuan F, Dellian M, Fukumura D et al (1995) Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res 55:3752–3756

    PubMed  CAS  Google Scholar 

  15. Neeman M, Provenzale JM, Dewhirst MW (2001) Magnetic resonance imaging applications in the evaluation of tumor angiogenesis. Semin Radiat Oncol 11:70–82

    Article  PubMed  CAS  Google Scholar 

  16. Dafni H, Gilead A, Nevo N et al (2003) Modulation of the pharmacokinetics of macromolecular contrast material by avidin chase: MRI, optical, and inductively coupled plasma mass spectrometry tracking of triply labeled albumin. Magn Reson Med 50:904–914

    Article  PubMed  CAS  Google Scholar 

  17. Schmiedl U, Brasch RC, Ogan MD et al (1990) Albumin labeled with Gd-DTPA. An intravascular contrast-enhancing agent for magnetic resonance blood pool and perfusion imaging. Acta Radiol Suppl 374:99–102

    PubMed  CAS  Google Scholar 

  18. van Dijke CF, Mann JS, Rosenau W et al (2002) Comparison of MR contrast-enhancing properties of albumin-(biotin)10-(gadopentetate)25, a macromolecular MR blood pool contrast agent, and its microscopic distribution. Acad Radiol 9(Suppl 1):S257–S260

    Article  PubMed  Google Scholar 

  19. Migalovich HS, Kalchenko V, Nevo N et al (2009) Harnessing competing endocytic pathways for overcoming the tumor-blood barrier: magnetic resonance imaging and near-infrared imaging of bifunctional contrast media. Cancer Res 69:5610–5617

    Article  PubMed  CAS  Google Scholar 

  20. Lauffer RB, Parmelee DJ, Dunham SU et al (1998) MS-325: albumin-targeted contrast agent for MR angiography. Radiology 207:529–538

    PubMed  CAS  Google Scholar 

  21. Caravan P, Cloutier NJ, Greenfield MT et al (2002) The interaction of MS-325 with human serum albumin and its effect on proton relaxation rates. J Am Chem Soc 124:3152–3162

    Article  PubMed  CAS  Google Scholar 

  22. Shamsi K, Yucel EK, Chamberlin P (2006) A summary of safety of gadofosveset (MS-325) at 0.03 mmol/kg body weight dose: Phase II and Phase III clinical trials data. Invest Radiol 41:822–830

    Article  PubMed  CAS  Google Scholar 

  23. Brasch RC (1992) New directions in the development of MR imaging contrast media. Radiology 183:1–11

    PubMed  CAS  Google Scholar 

  24. Brasch RC, Li KC, Husband JE et al (2000) In vivo monitoring of tumor angiogenesis with MR imaging. Acad Radiol 7:812–823

    Article  PubMed  CAS  Google Scholar 

  25. Bhujwalla ZM, Artemov D, Glockner J (1999) Tumor angiogenesis, vascularization, and contrast-enhanced magnetic resonance imaging. Top Magn Reson Imaging 10:92–103

    Article  PubMed  CAS  Google Scholar 

  26. Dafni H, Landsman L, Schechter B et al (2002) MRI and fluorescence microscopy of the acute vascular response to VEGF165: vasodilation, hyper-permeability and lymphatic uptake, followed by rapid inactivation of the growth factor. NMR Biomed 15:120–131

    Article  PubMed  CAS  Google Scholar 

  27. Brey EM, King TW, Johnston C et al (2002) A technique for quantitative three-dimensional analysis of microvascular structure. Microvasc Res 63:279–294

    Article  PubMed  Google Scholar 

  28. Samoszuk M, Leonor L, Espinoza F et al (2002) Measuring microvascular density in tumors by digital dissection. Anal Quant Cytol Histol 24:15–22

    PubMed  Google Scholar 

  29. Saeed M, van Dijke CF, Mann JS et al (1998) Histologic confirmation of microvascular hyperpermeability to macromolecular MR contrast medium in reperfused myocardial infarction. J Magn Reson Imaging 8:561–567

    Article  PubMed  CAS  Google Scholar 

  30. Dafni H, Israely T, Bhujwalla ZM et al (2002) Overexpression of vascular endothelial growth factor 165 drives peritumor interstitial convection and induces lymphatic drain: magnetic resonance imaging, confocal microscopy, and histological tracking of triple-labeled albumin. Cancer Res 62:6731–6739

    PubMed  CAS  Google Scholar 

  31. Folkman J (1992) The role of angiogenesis in tumor growth. Semin Cancer Biol 3:65–71

    PubMed  CAS  Google Scholar 

  32. Ravi R, Mookerjee B, Bhujwalla ZM et al (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14:34–44

    PubMed  CAS  Google Scholar 

  33. Sennino B, Raatschen HJ, Wendland MF et al (2009) Correlative dynamic contrast MRI and microscopic assessments of tumor vascularity in RIP-Tag2 transgenic mice. Magn Reson Med 62:616–625

    Article  PubMed  Google Scholar 

  34. Ali MM, Janic B, Babajani-Feremi A et al (2010) Changes in vascular permeability and expression of different angiogenic factors following anti-angiogenic treatment in rat glioma. PLoS One 5:e8727

    Article  PubMed  CAS  Google Scholar 

  35. Raatschen HJ, Simon GH, Fu Y et al (2008) Vascular permeability during antiangiogenesis treatment: MR imaging assay results as biomarker for subsequent tumor growth in rats. Radiology 247:391–399

    Article  PubMed  Google Scholar 

  36. Dafni H, Kim SJ, Bankson JA et al (2008) Macromolecular dynamic contrast-enhanced (DCE)-MRI detects reduced vascular permeability in a prostate cancer bone metastasis model following anti-platelet-derived growth factor receptor (PDGFR) therapy, indicating a drop in vascular endothelial growth factor receptor (VEGFR) activation. Magn Reson Med 60:822–833

    Article  PubMed  Google Scholar 

  37. Vogel-Claussen J, Gimi B, Artemov D et al (2007) Diffusion-weighted and macromolecular contrast enhanced MRI of tumor response to antivascular therapy with ZD6126. Cancer Biol Ther 6:1469–1475

    Article  PubMed  CAS  Google Scholar 

  38. Bhujwalla ZM, Artemov D, Natarajan K et al (2003) Reduction of vascular and permeable regions in solid tumors detected by macromolecular contrast magnetic resonance imaging after treatment with antiangiogenic agent TNP-470. Clin Cancer Res 9:355–362

    PubMed  CAS  Google Scholar 

  39. Gilad AA, Israely T, Dafni H et al (2005) Functional and molecular mapping of uncoupling between vascular permeability and loss of vascular maturation in ovarian carcinoma xenografts: the role of stroma cells in tumor angiogenesis. Int J Cancer 117:202–211

    Article  PubMed  CAS  Google Scholar 

  40. Bhujwalla ZM, Artemov D, Ballesteros P et al (2002) Combined vascular and extracellular pH imaging of solid tumors. NMR Biomed 15:114–119

    Article  PubMed  CAS  Google Scholar 

  41. Penet MF, Pathak AP, Raman V et al (2009) Noninvasive multiparametric imaging of metastasis-permissive microenvironments in a human prostate cancer xenograft. Cancer Res 69:8822–8829

    Article  PubMed  CAS  Google Scholar 

  42. Daldrup-Link HE, Brasch RC (2003) Macromolecular contrast agents for MR mammography: current status. Eur Radiol 13:354–365

    PubMed  Google Scholar 

  43. Cyran CC, Fu Y, Raatschen HJ et al (2008) New macromolecular polymeric MRI contrast agents for application in the differentiation of cancer from benign soft tissues. J Magn Reson Imaging 27:581–589

    Article  PubMed  Google Scholar 

  44. Preda A, Novikov V, Moglich M et al (2004) MRI monitoring of Avastin antiangiogenesis therapy using B22956/1, a new blood pool contrast agent, in an experimental model of human cancer. J Magn Reson Imaging 20:865–873

    Article  PubMed  Google Scholar 

  45. Feng Y, Jeong EK, Mohs AM et al (2008) Characterization of tumor angiogenesis with dynamic contrast-enhanced MRI and biodegradable macromolecular contrast agents in mice. Magn Reson Med 60:1347–1352

    Article  PubMed  Google Scholar 

  46. Senger DR, Brown LF, Claffey KP et al (1994) Vascular permeability factor, tumor angiogenesis and stroma generation. Invasion Metastasis 14:385–394

    PubMed  CAS  Google Scholar 

  47. Senger DR, Van de Water L, Brown LF et al (1993) Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev 12:303–324

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  49. Plaks V, Kalchenko V, Dekel N et al (2006) MRI analysis of angiogenesis during mouse embryo implantation. Magn Reson Med 55:1013–1022

    Article  PubMed  Google Scholar 

  50. Plaks V, Birnberg T, Berkutzki T et al (2008) Uterine DCs are crucial for decidua formation during embryo implantation in mice. J Clin Invest 118:3954–3965

    PubMed  CAS  Google Scholar 

  51. Vandoorne K, Magland J, Plaks V et al. (2010) Bone vascularization and trabecular bone formation are mediated by PKBalpha/Akt1 in a gene dosage dependent manner: In vivo and ex vivo MRI. Magn Reson Med (in press)

  52. Ziv K, Nevo N, Dafni H et al (2004) Longitudinal MRI tracking of the angiogenic response to hind limb ischemic injury in the mouse. Magn Reson Med 51:304–311

    Article  PubMed  Google Scholar 

  53. Pathak AP, Artemov D, Ward BD et al (2005) Characterizing extravascular fluid transport of macromolecules in the tumor interstitium by magnetic resonance imaging. Cancer Res 65:1425–1432

    Article  PubMed  CAS  Google Scholar 

  54. Saban MR, Towner R, Smith N et al. (2007) Lymphatic vessel density and function in experimental bladder cancer. 7:219

  55. Dafni H, Cohen B, Ziv K et al (2005) The role of heparanase in lymph node metastatic dissemination: dynamic contrast-enhanced MRI of Eb lymphoma in mice. Neoplasia 7:224–233

    Article  PubMed  CAS  Google Scholar 

  56. Israely T, Dafni H, Granot D et al (2003) Vascular remodeling and angiogenesis in ectopic ovarian transplants: a crucial role of pericytes and vascular smooth muscle cells in maintenance of ovarian grafts. Biol Reprod 68:2055–2064

    Article  PubMed  CAS  Google Scholar 

  57. Israely T, Dafni H, Nevo N et al (2004) Angiogenesis in ectopic ovarian xenotransplantation: multiparameter characterization of the neovasculature by dynamic contrast-enhanced MRI. Magn Reson Med 52:741–750

    Article  PubMed  Google Scholar 

  58. Ebert SN, Taylor DG, Nguyen HL et al (2007) Noninvasive tracking of cardiac embryonic stem cells in vivo using magnetic resonance imaging techniques. Stem Cells 25:2936–2944

    Article  PubMed  Google Scholar 

  59. Zhou B, Shan H, Li D et al. (2010) MR tracking of magnetically labeled mesenchymal stem cells in rats with liver fibrosis. Magn Reson Imaging

  60. Madisen L, Zwingman TA, Sunkin SM et al (2010) A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13:133–140

    Article  PubMed  CAS  Google Scholar 

  61. Granot D, Addadi Y, Kalchenko V et al (2007) In vivo imaging of the systemic recruitment of fibroblasts to the angiogenic rim of ovarian carcinoma tumors. Cancer Res 67:9180–9189

    Article  PubMed  CAS  Google Scholar 

  62. Granot D, Kunz-Schughart LA, Neeman M (2005) Labeling fibroblasts with biotin-BSA-GdDTPA-FAM for tracking of tumor-associated stroma by fluorescence and MR imaging. Magn Reson Med 54:789–797

    Article  PubMed  CAS  Google Scholar 

  63. Long CM, Bulte JW (2009) In vivo tracking of cellular therapeutics using magnetic resonance imaging. Expert Opin Biol Ther 9:293–306

    Article  PubMed  CAS  Google Scholar 

  64. Frank JA, Miller BR, Arbab AS et al (2003) Clinically applicable labeling of mammalian and stem cells by combining superparamagnetic iron oxides and transfection agents. Radiology 228:480–487

    Article  PubMed  Google Scholar 

  65. Baligand C, Vauchez K, Fiszman M et al (2009) Discrepancies between the fate of myoblast xenograft in mouse leg muscle and NMR label persistency after loading with Gd-DTPA or SPIOs. Gene Ther 16:734–745

    Article  PubMed  CAS  Google Scholar 

  66. Liu W, Frank JA (2009) Detection and quantification of magnetically labeled cells by cellular MRI. Eur J Radiol 70:258–264

    Article  PubMed  Google Scholar 

  67. Wang Z, Tiruppathi C, Minshall RD et al (2009) Size and dynamics of caveolae studied using nanoparticles in living endothelial cells. ACS Nano 3:4110–4116

    Article  PubMed  CAS  Google Scholar 

  68. Vogel SM, Minshall RD, Pilipovic M et al (2001) Albumin uptake and transcytosis in endothelial cells in vivo induced by albumin-binding protein. Am J Physiol Lung Cell Mol Physiol 281:L1512–L1522

    PubMed  CAS  Google Scholar 

  69. Phung TL, Ziv K, Dabydeen D et al (2006) Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10:159–170

    Article  PubMed  CAS  Google Scholar 

  70. Gilead A, Meir G, Neeman M (2004) The role of angiogenesis, vascular maturation, regression and stroma infiltration in dormancy and growth of implanted MLS ovarian carcinoma spheroids. Int J Cancer 108:524–531

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the USA NIH R01 CA75334, the DKFZ-MOST cooperational program, the Israel Science Foundation 93/07, The European Commission FP6 Integrated Project MEDITRANS, The European Commission FP7 Integrated Project ENCITE and European Research Council Advanced grant 232640-IMAGO (to MN), and by the Gurwin Foundation. Michal Neeman is incumbent of the Helen and Morris Mauerberger Chair.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michal Neeman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vandoorne, K., Addadi, Y. & Neeman, M. Visualizing vascular permeability and lymphatic drainage using labeled serum albumin. Angiogenesis 13, 75–85 (2010). https://doi.org/10.1007/s10456-010-9170-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-010-9170-4

Keywords

Navigation