This Article Full Text Full Text (PDF) All Versions of this Article: 107/3/455    most recent 01.CIR.0000044916.05919.8Bv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Leong-Poi, H. Articles by Lindner, J. R. Search for Related Content PubMed PubMed Citation Articles by Leong-Poi, H. Articles by Lindner, J. R. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Ultrasound Related Collections Cardiovascular imaging agents/Techniques Angiogenesis

(Circulation. 2003;107:455.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Noninvasive Assessment of Angiogenesis by Ultrasound and Microbubbles Targeted to _v-Integrins

Howard Leong-Poi, MD; Jonathan Christiansen, MB ChB; Alexander L. Klibanov, PhD; Sanjiv Kaul, MD; Jonathan R. Lindner, MD

From the Cardiovascular Imaging Center, Cardiovascular Division, University of Virginia, Charlottesville.

Correspondence to Jonathan R. Lindner, MD, Box 800158, Cardiovascular Division, University of Virginia Medical Center, Charlottesville, VA 22908. E-mail jlindner{at}virginia.edu

Background— Noninvasive methods for characterizing neovessel formation during angiogenesis are currently lacking. We hypothesized that angiogenesis could be imaged with the use of contrast-enhanced ultrasound (CEU) with microbubbles targeted to _v-integrins.

Methods and Results— Microbubbles targeted to _v-integrins were prepared by conjugating echistatin (MB_E) or monoclonal antibody against murine _v (MB) to their surface. Control microbubbles (MB_c) were also prepared. The microvascular behavior of these microbubbles was assessed by intravital microscopy of the cremaster muscle in mice treated for 4 days with sustained-release FGF-2. Microvascular retention was much greater (P<0.01) for MB_E (11±6 mm^-3) and MB (10±7 mm^-3) than that for MB_c (1±1 mm^-3). Retained MB_E and MB attached directly to the microvascular endothelial surface. Microbubble retention in 4 control mice was minimal. Subcutaneous matrigel plugs enriched with FGF-2 were created in 12 mice and studied 10 days later. Neovessels within the matrigel stained positive for _v-integrins. CEU demonstrated greater (P<0.01) acoustic intensity for MB_E (16.0±5.9 U) and MB (17.0±5.5 U) compared with MB_c (5.8±2.6 U). The signal from targeted microbubbles (MB_E and MB) correlated well (r=0.90) with the matrigel blood volume determined by CEU perfusion imaging.

Conclusions— CEU with microbubbles targeted for _v-integrins may provide a noninvasive method for assessing therapeutic angiogenesis.

Key Words: angiogenesis • echocardiography • microcirculation

This article has been cited by other articles:

				R. P. Choudhury and E. A. Fisher Molecular Imaging in Atherosclerosis, Thrombosis, and Vascular Inflammation Arterioscler. Thromb. Vasc. Biol., July 1, 2009; 29(7): 983 - 991. [Abstract] [Full Text] [PDF]

				D. TILKI, M. SEITZ, B. B. SINGER, S. IRMAK, C. G. STIEF, O. REICH, and S. ERGUN Molecular Imaging of Tumor Blood Vessels in Prostate Cancer Anticancer Res, May 1, 2009; 29(5): 1823 - 1829. [Abstract] [Full Text] [PDF]

				S. Kaul Myocardial Contrast Echocardiography: A 25-Year Retrospective Circulation, July 15, 2008; 118(3): 291 - 308. [Full Text] [PDF]

				C. Z. Behm, B. A. Kaufmann, C. Carr, M. Lankford, J. M. Sanders, C. E. Rose, S. Kaul, and J. R. Lindner Molecular Imaging of Endothelial Vascular Cell Adhesion Molecule-1 Expression and Inflammatory Cell Recruitment During Vasculogenesis and Ischemia-Mediated Arteriogenesis Circulation, June 3, 2008; 117(22): 2902 - 2911. [Abstract] [Full Text] [PDF]

				D. J. Lee, A. Lyshchik, J. Huamani, D. E. Hallahan, and A. C. Fleischer Relationship Between Retention of a Vascular Endothelial Growth Factor Receptor 2 (VEGFR2)-Targeted Ultrasonographic Contrast Agent and the Level of VEGFR2 Expression in an In Vivo Breast Cancer Model J. Ultrasound Med., June 1, 2008; 27(6): 855 - 866. [Abstract] [Full Text] [PDF]

				L. H. Clerk, M. A. Vincent, E. J. Barrett, M. F. Lankford, and J. R. Lindner Skeletal muscle capillary responses to insulin are abnormal in late-stage diabetes and are restored by angiogensin-converting enzyme inhibition Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1804 - E1809. [Abstract] [Full Text] [PDF]

				A. Lyshchik, A. C. Fleischer, J. Huamani, D. E. Hallahan, M. Brissova, and J. C. Gore Molecular Imaging of Vascular Endothelial Growth Factor Receptor 2 Expression Using Targeted Contrast-Enhanced High-Frequency Ultrasonography J. Ultrasound Med., November 1, 2007; 26(11): 1575 - 1586. [Abstract] [Full Text] [PDF]

				T. R. Porter Cardiovascular Imaging of Remote Myocardial Ischemia: Detecting a Molecular Trace of Evidence Left Behind Circulation, January 23, 2007; 115(3): 292 - 293. [Full Text] [PDF]

				F. S. Villanueva, E. Lu, S. Bowry, S. Kilic, E. Tom, J. Wang, J. Gretton, J. J. Pacella, and W. R. Wagner Myocardial Ischemic Memory Imaging With Molecular Echocardiography Circulation, January 23, 2007; 115(3): 345 - 352. [Abstract] [Full Text] [PDF]

				R. Vogel, R. Zbinden, A. Indermuhle, S. Windecker, B. Meier, and C. Seiler Collateral-flow measurements in humans by myocardial contrast echocardiography: validation of coronary pressure-derived collateral-flow assessment Eur. Heart J., January 2, 2006; 27(2): 157 - 165. [Abstract] [Full Text] [PDF]

				X. Zhang, Z. Xiong, Y. Wu, W. Cai, J. R. Tseng, S. S. Gambhir, and X. Chen Quantitative PET Imaging of Tumor Integrin {alpha}v{beta}3 Expression with 18F-FRGD2 J. Nucl. Med., January 1, 2006; 47(1): 113 - 121. [Abstract] [Full Text] [PDF]

				P. Hauff, S. Seemann, R. Reszka, M. Schultze-Mosgau, M. Reinhardt, T. Buzasi, T. Plath, S. Rosewicz, and M. Schirner Evaluation of Gas-filled Microparticles and Sonoporation as Gene Delivery System: Feasibility Study in Rodent Tumor Models Radiology, August 1, 2005; 236(2): 572 - 578. [Abstract] [Full Text] [PDF]

				H. Leong-Poi, J. Christiansen, P. Heppner, C. W. Lewis, A. L. Klibanov, S. Kaul, and J. R. Lindner Assessment of Endogenous and Therapeutic Arteriogenesis by Contrast Ultrasound Molecular Imaging of Integrin Expression Circulation, June 21, 2005; 111(24): 3248 - 3254. [Abstract] [Full Text] [PDF]

				T. Sakuma, I. Sari, C. N. Goodman, J. R. Lindner, A. L. Klibanov, and S. Kaul Simultaneous integrin {alpha}v{beta}3 and glycoprotein IIb/IIIa inhibition causes reduction in infarct size in a model of acute coronary thrombosis and primary angioplasty Cardiovasc Res, June 1, 2005; 66(3): 552 - 561. [Abstract] [Full Text] [PDF]

				J. S. Abramowicz Ultrasonographic Contrast Media: Has the Time Come in Obstetrics and Gynecology? J. Ultrasound Med., April 1, 2005; 24(4): 517 - 531. [Abstract] [Full Text] [PDF]

				K.-H. Lee, K.-H. Jung, S.-H. Song, D. H. Kim, B. C. Lee, H. J. Sung, Y.-M. Han, Y. S. Choe, D. Y. Chi, and B.-T. Kim Radiolabeled RGD Uptake and {alpha}v Integrin Expression Is Enhanced in Ischemic Murine Hindlimbs J. Nucl. Med., March 1, 2005; 46(3): 472 - 478. [Abstract] [Full Text] [PDF]

				G. E.R. Weller, M. K.K. Wong, R. A. Modzelewski, E. Lu, A. L. Klibanov, W. R. Wagner, and F. S. Villanueva Ultrasonic Imaging of Tumor Angiogenesis Using Contrast Microbubbles Targeted via the Tumor-Binding Peptide Arginine-Arginine-Leucine Cancer Res., January 15, 2005; 65(2): 533 - 539. [Abstract] [Full Text] [PDF]

				A. C. Fleischer, K. J. Niermann, E. F. Donnelly, T. E. Yankeelov, K. M. Canniff, D. E. Hallahan, and M. E. Rothenberg Sonographic Depiction of Microvessel Perfusion: Principles and Potential J. Ultrasound Med., November 1, 2004; 23(11): 1499 - 1506. [Abstract] [Full Text] [PDF]

				P. R. Moreno, K. R. Purushothaman, V. Fuster, D. Echeverri, H. Truszczynska, S. K. Sharma, J. J. Badimon, and W. N. O'Connor Plaque Neovascularization Is Increased in Ruptured Atherosclerotic Lesions of Human Aorta: Implications for Plaque Vulnerability Circulation, October 5, 2004; 110(14): 2032 - 2038. [Abstract] [Full Text] [PDF]

				P.A Dijkmans, L.J.M Juffermans, R.J.P Musters, A van Wamel, F.J ten Cate, W van Gilst, C.A Visser, N de Jong, and O Kamp Microbubbles and ultrasound: from diagnosis to therapy Eur J Echocardiogr, August 1, 2004; 5(4): 245 - 246. [Abstract] [Full Text] [PDF]

				P. Hauff, M. Reinhardt, A. Briel, N. Debus, and M. Schirner Molecular Targeting of Lymph Nodes with L-Selectin Ligand-specific US Contrast Agent: A Feasibility Study in Mice and Dogs Radiology, June 1, 2004; 231(3): 667 - 673. [Abstract] [Full Text] [PDF]

				F. A. Jaffer and R. Weissleder Seeing Within: Molecular Imaging of the Cardiovascular System Circ. Res., March 5, 2004; 94(4): 433 - 445. [Abstract] [Full Text] [PDF]

				S. Kaul and J. R. Lindner Visualizing coronary atherosclerosis in vivo: thinking big, imaging small J. Am. Coll. Cardiol., February 4, 2004; 43(3): 461 - 463. [Full Text] [PDF]

				C. R. Anderson, A. M. Ponce, and R. J. Price Absence of OX-43 antigen expression in invasive capillary sprouts: identification of a capillary sprout-specific endothelial phenotype Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H346 - H353. [Abstract] [Full Text] [PDF]

				D Cosgrove Angiogenesis imaging - ultrasound Br. J. Radiol., December 1, 2003; 76(suppl_1): S43 - S49. [Full Text] [PDF]

				S M Galbraith Antivascular cancer treatments: imaging biomarkers in pharmaceutical drug development Br. J. Radiol., December 1, 2003; 76(suppl_1): S83 - S86. [Full Text] [PDF]

				M. Blomley Which US Microbubble Contrast Agent Is Best for Gene Therapy? Radiology, November 1, 2003; 229(2): 297 - 298. [Full Text] [PDF]

				D. B. Ellegala, H. Leong-Poi, J. E. Carpenter, A. L. Klibanov, S. Kaul, M. E. Shaffrey, J. Sklenar, and J. R. Lindner Imaging Tumor Angiogenesis With Contrast Ultrasound and Microbubbles Targeted to {alpha}v{beta}3 Circulation, July 22, 2003; 108(3): 336 - 341. [Abstract] [Full Text] [PDF]