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Consensus Guidelines for the Use and Interpretation of Angiogenesis Assays

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Consensus Guidelines for the Use and Interpretation of Angiogenesis Assays Angiogenesis (2018) 21:425–532 https://doi.org/10.1007/s10456-018-9613-x REVIEW PAPER Consensus guidelines for the use and interpretation of angiogenesis assays Patrycja Nowak‑Sliwinska1,2 · Kari Alitalo3 · Elizabeth Allen4 · Andrey Anisimov3 · Alfred C. Aplin5 · Robert Auerbach6 · Hellmut G. Augustin7,8,9 · David O. Bates10 · Judy R. van Beijnum11 · R. Hugh F. Bender12 · Gabriele Bergers13,4 · Andreas Bikfalvi14 · Joyce Bischof15 · Barbara C. Böck7,8,9 · Peter C. Brooks16 · Federico Bussolino17,18 · Bertan Cakir19 · Peter Carmeliet20,21 · Daniel Castranova22 · Anca M. Cimpean23 · Ondine Cleaver24 · George Coukos25 · George E. Davis26 · Michele De Palma27 · Anna Dimberg28 · Ruud P. M. Dings29 · Valentin Djonov30 · Andrew C. Dudley31,32 · Neil P. Dufton33 · Sarah‑Maria Fendt34,35 · Napoleone Ferrara36 · Marcus Fruttiger37 · Dai Fukumura38 · Bart Ghesquière39,40 · Yan Gong19 · Robert J. Grifn29 · Adrian L. Harris41 · Christopher C. W. Hughes12 · Nan W. Hultgren12 · M. Luisa Iruela‑Arispe42 · Melita Irving25 · Rakesh K. Jain38 · Raghu Kalluri43 · Joanna Kalucka20,21 · Robert S. Kerbel44 · Jan Kitajewski45 · Ingeborg Klaassen46 · Hynda K. Kleinmann47 · Pieter Koolwijk48 · Elisabeth Kuczynski44 · Brenda R. Kwak49 · Koen Marien50 · Juan M. Melero‑Martin51 · Lance L. Munn38 · Roberto F. Nicosia5,52 · Agnes Noel53 · Jussi Nurro54 · Anna‑Karin Olsson55 · Tatiana V. Petrova56 · Kristian Pietras57 · Roberto Pili58 · Jefrey W. Pollard59 · Mark J. Post60 · Paul H. A. Quax61 · Gabriel A. Rabinovich62 · Marius Raica23 · Anna M. Randi33 · Domenico Ribatti63,64 · Curzio Ruegg65 · Reinier O. Schlingemann46,48 · Stefan Schulte‑Merker66 · Lois E. H. Smith19 · Jonathan W. Song67,68 · Steven A. Stacker69 · Jimmy Stalin66 · Amber N. Stratman22 · Maureen Van de Velde53 · Victor W. M. van Hinsbergh48 · Peter B. Vermeulen50,72 · Johannes Waltenberger70 · Brant M. Weinstein22 · Hong Xin36 · Bahar Yetkin‑Arik46 · Seppo Yla‑Herttuala54 · Mervin C. Yoder71 · Arjan W. Grifoen11 Published online: 15 May 2018 © The Author(s) 2018 Abstract The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and develop- ment, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantifed by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the frst edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference. Keywords Angiogenesis · Aortic ring · Endothelial cell migration · Proliferation · Microfuidic · Zebrafsh · Chorioallantoic membrane (CAM) · Vascular network · Intussusceptive angiogenesis · Retinal vasculature · Corneal angiogenesis · Hindlimb ischemia · Myocardial angiogenesis · Recombinant proteins · Tip cells · Plug assay · Myocardial angiogenesis · Vessel co-option Table of contents 1. Introduction 2. Endothelial cell and monocyte migration assays * Patrycja Nowak‑Sliwinska 3. Endothelial cell proliferation assays Patrycja.Nowak‑[email protected] 4. 3D models of vascular morphogenesis * Arjan W. Grifoen 5. Aortic ring assay [email protected] 6. Tumor microvessel density and histopathological growth patterns in tumors Extended author information available on the last page of the article Vol.:(0123456789)1 3 426 Angiogenesis (2018) 21:425–532 7. Assessment of intussusceptive angiogenesis angiogenesis, inherently implies accepting specifc limita- 8. In vivo sprouting lymphangiogenic assay and AAV-mediated gene tions. It is therefore crucial to understand the full potential transfer of vascular endothelial growth factor c (VEGFC) of these bioassays during their specifc applications. These 9. Assay for pericyte recruitment to endothelial cell-lined tubes, assays have been instrumental in the study of vascular biol- capillary assembly, and maturation ogy in growth and development [6–8] but also play a key 10. EC co-culture spheroids role in the design, development, and evaluation of drugs 11. Endothelial cell metabolism that positively or negatively modulate vessel function for 12. Endothelial cell precursors the treatment of many diseases [9–11]. Some examples of 13. Microfuidic assays where the use of such bioassays has been imperative are: 14. Flow cytometry and cell sorting assays (1) the development of angiostatic drugs for the treatment 15. Loss-of-function approaches in the developing zebrafsh of cancer, ocular diseases, and other pathologic conditions 16. Chorioallantoic membrane assays where angiogenesis is implicated and also angiogenic treat- 17. Murine allantois assay ment strategies in ischemic cardiovascular disease [12, 13], 18. In vivo angiogenesis plug assay (2) screening of natural anti-angiogenic compounds [14], (3) 19. In vivo vascular network forming assay the eforts to design combination therapies including angio- 20. Developing mouse retinal vasculature—tip cells genesis inhibitors [15–20], (4) the unraveling of mechanisms 21. Corneal angiogenesis assays regulating lymphangiogenesis [21, 22], (5) the interrelation- 22. Mouse oxygen-induced retinopathy model ship of angiogenesis and immunity [23–25], (6) the develop- 23. Laser-induced choroidal neovascularization mouse model ment of imaging as diagnostic strategy [26], (7) the study 24. Transparent window preparations for angiogenesis studies in mice of drug resistance mechanisms [27–29], (8) development 25. The RIP1-Tag2 transgenic mouse model of compounds and strategies for the revascularization of 26. The MMTV-PyMT breast cancer model ischemic injuries [30, 31], and (9) to improve the vascular 27. Tumor implantation models ftness in aging vessels [32, 33]. The current paper describes 28. Mouse hind limb ischemia model a large collection of assays and techniques for the evalua- 29. Large animal models for myocardial angiogenesis tion of angiogenesis and aims at explaining their respec- 30. Guidelines for purity of recombinant proteins in angiogenesis tive advantages and limitations. In addition, we included assays strategies to study angiogenesis in tissues, through means 31. Conclusions of assessing and quantifying microvessel density (MVD), vessel co-option, pericyte coverage, and tip cell behavior. 1 Introduction The process of angiogenesis—the formation of new blood 2 Endothelial cell and monocyte migration vessels from preexisting ones—is a hallmark of tissue repair, assays expansion, and remodeling in physiological processes, such as wound healing, ovulation, and embryo development, and EC migration is one of the hallmarks of angiogenesis and in various pathologies including cancer, atherosclerosis, one of the earlier steps in the angiogenic cascade. This and chronic infammation [1–5]. Many of these conditions process is characterized by cell-autonomous motility prop- share characteristics, for example the occurrence of hypoxia erty but in some cases, it acquires the features of collective or infammation, recruitment of infammatory cells, angio- migration [34–37], in which a group of cells coordinate their genic growth factor production, basement membrane deg- movements toward a chemotactic gradient and by estab- radation, endothelial cell (EC) migration, proliferation and lishing a precise hierarchy with leader and follower cells. diferentiation, and modulation of vascular support cells. Therefore, dissection of the molecular mechanisms of EC However, depending on the tissue or disease under inves- migration is critical to understand and to therapeutically tigation, important details may difer considerably. Moreo- manipulate the process to either inhibit sprouting (e.g., in ver, EC in diferent vascular beds exhibits organ-specifc tumors) or stimulate vessel formation (e.g., during tissue heterogeneity associated with the diferentiated specialized regeneration or wound healing). functions of the tissue. It is often not possible to accurately Likewise, migration assays have been successfully used visualize the process of angiogenesis and its molecular to assess the migratory responsiveness of monocytes. players. Therefore, diferent in vivo, ex vivo, and in vitro Monocytes are actively involved in angiogenesis, and their bioassays and techniques have been developed to investi- migratory response or potential correlates well with that of gate the specifc stages of the angiogenesis. However, the endothelial cells. Most importantly, CD14-positive mono- use of bioassays that study a part of the process, with the cytes can easily be isolated and obtained from any individ- intention to extrapolate and understand the full process of ual, not only humans [38, 39], but also mice [40]. A number 1 3 Angiogenesis (2018) 21:425–532 427 of 2D and 3D cellular migration assays have been estab- phenotype with prominent stress fbers, rufing lamellipodia lished as relatively simple in vitro readouts of the migratory/ and enlarged focal adhesions, formation of peripheral actin angiogenic activity of EC in response to exogenous stimuli. cables, and discontinuous adherens junctions, which indicate Depending on the specifc scientifc question, a range of mechanical coupling between leader and follower cells in assays is available to quantitatively and qualitatively assess the migrating cluster [47]; (3) as leaders
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