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Imaging of angiogenesis: from microscope to clinic

Abstract

Advances in imaging are transforming our understanding of angiogenesis and the evaluation of drugs that stimulate or inhibit angiogenesis in preclinical models and human disease. Vascular imaging makes it possible to quantify the number and spacing of blood vessels, measure blood flow and vascular permeability, and analyze cellular and molecular abnormalities in blood vessel walls. Microscopic methods ranging from fluorescence, confocal and multiphoton microscopy to electron microscopic imaging are particularly useful for elucidating structural and functional abnormalities of angiogenic blood vessels. Magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), ultrasonography and optical imaging provide noninvasive, functionally relevant images of angiogenesis in animals and humans. An ongoing dilemma is, however, that microscopic methods provide their highest resolution on preserved tissue specimens, whereas clinical methods give images of living tissues deep within the body but at much lower resolution and specificity and generally cannot resolve vessels of the microcirculation. Future challenges include developing new imaging methods that can bridge this resolution gap and specifically identify angiogenic vessels. Another goal is to determine which microscopic techniques are the best benchmarks for interpreting clinical images. The importance of angiogenesis in cancer, chronic inflammatory diseases, age-related macular degeneration and reversal of ischemic heart and limb disease provides incentive for meeting these challenges.

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Figure 1: Microscopic imaging of normal and angiogenic blood vessels.
Figure 2: In vivo imaging of human tumors and structural basis of tumor vessel leakiness.
Figure 3: Imaging of leakage-based targeting and vascular targeting in tumors.
Figure 4: Imaging of tumor vessel pericytes, basement membrane and perivascular sleeves.
Figure 5: Imaging of tumor hypoxia and effects of angiogenesis inhibitors.
Figure 6: Dynamic enhanced MRI of breast cancer before and after treatment.

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Acknowledgements

We thank P. Baluk, H. Hashizume, A. Haskell, T. Inai, I. Kasman, M. Mancuso and S. Morikawa (all in the McDonald lab), M. Krishna (National Cancer Institute), and M. Konerding (University of Mainz, Germany) for supplying many of the images; R. Pasqualini and W. Arap (M.D. Anderson Cancer Center, Houston), and V. Yao and M. Ozawa (University of California, San Francisco) for the RGD-4C phage; R. Brekken (University of Washington) for the antibody to VEGFR-2; A. Uemura (Kyoto University, Japan), for the antibody to PDGFR-β; and G. Thurston (Regeneron Pharmaceuticals) for the VEGF-Trap. Supported in part by National Institutes of Health grants HL-24136 and HL-59157 from the National, Heart, Lung and Blood Institute and P50-CA90270 from the National Cancer Institute, University of California BioSTAR Project 00-10106 in conjunction with Eos Biotechnology, Inc., and funding from AngelWorks Foundation and the Vascular Mapping Project (D.M.M.).

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McDonald, D., Choyke, P. Imaging of angiogenesis: from microscope to clinic. Nat Med 9, 713–725 (2003). https://doi.org/10.1038/nm0603-713

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