In vitro angiogenesis: endothelial cell tube formation on gelled basement membrane extract
Abstract
A protocol is presented here for a rapid, quantitative and reliable in vitro angiogenesis assay that can be adapted for high throughput use. Endothelial cells are plated on a gelled basement matrix, their natural substrate, and form capillary-like structures with a lumen. The assay can be used to identify inhibitors or stimulators of angiogenesis, as well as genes and signaling pathways involved in angiogenesis. It has also been used to identify endothelial progenitor cells. This assay involves endothelial cell adhesion, migration, protease activity and tubule formation. This tube formation assay is preferred, as other in vitro assays for angiogenesis, such as cell adhesion, migration and invasion, measure limited steps in the angiogenesis process. The tube formation assay on basement membrane can be completed in a day because transformed endothelial cells form tubes within 3 h, whereas non-transformed endothelial cells form tubes within 6 h.
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The assays used to measure endothelial function robustly assess endothelial cell health.
“together, the assays robustly assess the health of ECs.”
From An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging (2021) · cites this paper as [53]
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“The vasculogenesis assay was performed as described in [53], by using the thick gel method of preparation.”
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A cerium oxide loaded glycol chitosan nano-system for the treatment of dry eye disease
Fan, Y., Zheng, M., Zhang, A. Y., & Han, Z. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.10.039 · Cited by 117 · see citing works
“In vitro primary corneal and conjunctival migration assay were performed in this study [40, 41].”
MethodChoi, H. Y., Moon, S. J., Ratliff, B. B., Ahn, S. H., Jung, A., Lee, M., Lee, S., Lim, B. J., Kim, B. S., Plotkin, M. D., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087853 · Cited by 112 · see citing works
In vitro assays and techniques utilized in anticancer drug discovery
Ediriweera, M. K., Tennekoon, K. H., & Samarakoon, S. R. (2018) · Journal of Applied Toxicology · doi:10.1002/jat.3658 · Cited by 112 · see citing works
Fridman, R., Benton, G., Aranoutova, I., Kleinman, H. K., & Bonfil, R. D. (2012) · Nature Protocols · doi:10.1038/nprot.2012.053 · Cited by 105 · see citing works
Self-citationLi, M., Xu, Z., Zhang, L., Cui, M., Zhu, M., Guo, Y., Sun, R., Han, J., Song, E., He, Y., et al. (2021) · ACS Nano · doi:10.1021/acsnano.1c00680 · Cited by 105 · see citing works
Ba, Q., Li, J., Huang, C., Qiu, H., Li, J., Chu, R., Zhang, W., Xie, D., Wu, Y., & Wang, H. (2014) · Environmental Health Perspectives · doi:10.1289/ehp.1408524 · Cited by 104 · see citing works
Du, S., Yang, Z., Lu, X., Yousuf, S., Zhao, M., Li, W., Miao, J., Wang, X., Heng, Y., Zhu, X., et al. (2021) · Oncogene · doi:10.1038/s41388-021-01988-y · Cited by 102 · see citing works
“We next investigated and compared the ability of GC and GC cells in promoting the formation of 3D capillary-like tubular structure of HUVEC on the matrigel that mimics basement membrane matrix, encompassing all steps of angiogenesis [25].”
Agrin Promotes Coordinated Therapeutic Processes Leading to Improved Cardiac Repair in Pigs
Baehr, A., Umansky, K. B., Bassat, E., Klett, K., Jurisch, V., Bozoglu, T. M., Hornaschewitz, N., Solyanik, O., Kain, D., Ferraro, B., et al. (2020) · Circulation · doi:10.1161/circulationaha.119.045116 · Cited by 101 · see citing works
“For HUVEC tube formation, we used awell established protocol, described in (37).”
BackgroundMethodVascular tube formation and angiogenesis induced by polyvinylpyrrolidone-coated silver nanoparticles
Kang, K., Lim, D.-H., Choi, I., Kang, T., Lee, K., Moon, E.-Y., Yang, Y. D., Lee, M.-S., & Lim, J. (2011) · Toxicology Letters · doi:10.1016/j.toxlet.2011.05.1033 · Cited by 101 · see citing works
Molecular mechanism inhibiting human hepatocarcinoma cell invasion by 6‐shogaol and 6‐gingerol
Weng, C., Chou, C., Ho, C., & Yen, G. (2012) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201200173 · Cited by 96 · see citing works
Transient Receptor Potential Canonical Channels Are Required for in Vitro Endothelial Tube Formation
Antigny, F., Girardin, N., & Frieden, M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.295733 · Cited by 95 · see citing works
Development and Validation of an Automated High-Throughput System for Zebrafish In Vivo Screenings
Letamendı́a, A., Quevedo, C., Ibarbia, I., Virto, J. M., Holgado, O., Diez, M., Belmonte, J. C. I., & Callol-Massot, C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0036690 · Cited by 94 · see citing works
“The preferred in vitro method for assessing angiogeneic regulators is endothelial cell tube formation assay [44], [45], [46], [47].”
MethodHulsurkar, M. M., Li, Z., Zhang, Y., Li, X., Zheng, D., & Li, W. (2016) · Oncogene · doi:10.1038/onc.2016.319 · Cited by 95 · see citing works
Mitra, R. N., Gao, R., Zheng, M., Wu, M. J., Voinov, M. A., Smirnov, A. I., Smirnova, T. I., Wang, K., Chavala, S. H., & Han, Z. (2017) · ACS Nano · doi:10.1021/acsnano.7b00429 · Cited by 94 · see citing works
Jin, R., Song, G., Chai, J., Gou, X., Yuan, G., & Chen, Z. (2018) · Journal of Tissue Engineering · doi:10.1177/2041731418817505 · Cited by 91 · see citing works
Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression
Ferrarese, R., Harsh, G. R., Yadav, A. K., Bug, E., Maticzka, D., Reichardt, W., Dombrowski, S. M., Miller, T. E., Masilamani, A. P., Dai, F., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci68836 · Cited by 92 · see citing works
“This assay measures the ability of ECs, plated at subconfluent densities with the appropriate extracellular matrix support, to form capillary-like structures (aka tubes) (79).”
Fu, J., Wei, C., Zhang, W., Schlöndorff, D., Wu, J., Cai, M., Wu, H., Baron, M. H., Chuang, P. Y., Liu, Z., et al. (2018) · Kidney International · doi:10.1016/j.kint.2018.02.028 · Cited by 89 · see citing works
Secreted Threonyl-tRNA synthetase stimulates endothelial cell migration and angiogenesis
Williams, T. F., Mirando, A. C., Wilkinson, B. M., Francklyn, C. S., & Lounsbury, K. M. (2013) · Scientific Reports · doi:10.1038/srep01317 · Cited by 88 · see citing works
Lee, S. J., Yook, S., Yhee, J. Y., Yoon, H. Y., Kim, M.-G., Ku, S. H., Kim, S. H., Park, J. H., Jeong, J. H., Kwon, I. C., et al. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.08.032 · Cited by 87 · see citing works
Liu, J., Wu, X., Lu, J. G., Huang, G., Dang, L., Zhang, H., Zhong, C., Zhang, Z., Li, D., Li, F., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00050-6 · Cited by 85 · see citing works
Lin, W.-C., Huang, C., Lin, S., Li, M., Chang, Y., Lin, Y., Wan, W., Shih, P., & Sung, H. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2017.08.023 · Cited by 83 · see citing works
“The residual gaps between the migrating c ells were measured and expressed as a percentage of the original cell-free area using Ima geJ software [18].”
MethodCell alignment and accumulation using acoustic nozzle for bioprinting
Sriphutkiat, Y., Kasetsirikul, S., Ketpun, D., & Zhou, Y. (2019) · Scientific Reports · doi:10.1038/s41598-019-54330-8 · Cited by 83 · see citing works
Targeted intervention in nerve–cancer crosstalk enhances pancreatic cancer chemotherapy
Qin, J., Liu, J., Wei, Z., Li, X., Chen, Z., Li, J., Zheng, W., Liu, H., Xu, S., Yong, T., et al. (2024) · Nature Nanotechnology · doi:10.1038/s41565-024-01803-1 · Cited by 83 · see citing works
“The migration and capillary tube formation of endothelial cells were essential for angiogenesis 42 .”
Techniques and assays for the study of angiogenesis
Irvin, M., Zijlstra, A., Wikswo, J. P., & Pozzi, A. (2014) · Experimental Biology and Medicine · doi:10.1177/1535370214529386 · Cited by 81 · see citing works
Lee, J., Lee, S., Ahmad, T., Perikamana, S. K. M., Lee, J., Kim, E. M., & Shin, H. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120192 · Cited by 79 · see citing works
Cui, J., Yu, X., Yu, B., Yang, X., Fu, Z., Wan, J., Zhu, M., Wang, X., & Lin, K. (2022) · Advanced Healthcare Materials · doi:10.1002/adhm.202200571 · Cited by 78 · see citing works
Calcitonin gene-related peptide promotes angiogenesis via AMP-activated protein kinase
Zheng, S., Li, W., Xu, M., Bai, X., Zhou, Z., Han, J., Shyy, J. Y.-J., & Wang, X. (2010) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00173.2010 · Cited by 79 · see citing works
“According to published methods (1), the degree of tube formation was quantified by measuring the number of tubes tube-like structures in five randomly chosen fields ( 100) from each dish using the NIH Image Program.”
MethodStamati, K., Priestley, J. V., Mudera, V., & Cheema, U. (2014) · Experimental Cell Research · doi:10.1016/j.yexcr.2014.05.012 · Cited by 78 · see citing works
Ge, Y., Wang, Q., Yao, Y., Qin, X., Sun, J., Chen, W., Lin, Y., & Cai, X. (2024) · Advanced Science · doi:10.1002/advs.202308701 · Cited by 76 · see citing works
Sialylation of vasorin by ST3Gal1 facilitates TGF‐β1‐mediated tumor angiogenesis and progression
Yeo, H. L., Fan, T.-C., Lin, R., Yu, J., Liao, G., Chen, E. S.-W., Ho, M., Lin, W., Chen, K., Chen, C., et al. (2018) · International Journal of Cancer · doi:10.1002/ijc.31891 · Cited by 75 · see citing works
“Endothelial cell tube formation The endothelial cell tube formation assay was performed as previously described.(20) Matrigel (BD, Bedford, MA) was added to 48-well plates in a volume of 150 μL and allowed to solidify at 37 C for 30 min.”
MethodAutoTube: a novel software for the automated morphometric analysis of vascular networks in tissues
Zegarra, J. A. M., Russo, E., Runge, P., Jadhav, M., Willrodt, A., Stoma, S., Nørrelykke, S. F., Detmar, M. J., & Halin, C. (2018) · Angiogenesis · doi:10.1007/s10456-018-9652-3 · Cited by 73 · see citing works
“In these assays, the formation of vessel-like structures (tubes) by endothelial cells in gels containing extracellular matrix components is captured in 2D-microscopic images at a specific time point, followed by an imagebased quantitative analysis of the vascular network (most importantly of tube length) [13, 14].”
MethodDuan, T., Xu, Z., Sun, F., Wang, Y., Zhang, J., Luo, C., & Wang, M. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109121 · Cited by 73 · see citing works
Smooth muscle SIRT1 reprograms endothelial cells to suppress angiogenesis after ischemia
Dou, Y., Kong, P., Li, C., Sun, H., Li, W., Yuan, Y. J., Nie, L., Zhao, L., Miao, S., Li, X., et al. (2020) · Theranostics · doi:10.7150/thno.39320 · Cited by 72 · see citing works
“The tube formation assay is a preferred protocol to identify inhibitors or stimulators of the angiogenic activity of ECs in vitro [34].”
MethodHove, A. H. V., Beltejar, M.-J. G., & Benoit, D. S. W. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.08.019 · Cited by 71 · see citing works
“(Pathology Devices) on a Nikon Eclipse Ti 2000 inverted light microscope [37].”
Wu, H., Zhang, X., Han, D., Cao, J., & Tian, J. (2020) · PeerJ · doi:10.7717/peerj.8721 · Cited by 70 · see citing works
Chorioallantoic Membrane Assay as Model for Angiogenesis in Tissue Engineering: Focus on Stem Cells
Merckx, G., Tay, H., Monaco, M. L., van Zandvoort, M. A. M. J., Spiegelaere, W. D., Lambrichts, I., & Bronckaers, A. (2020) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2020.0048 · Cited by 70 · see citing works
“Finally, vessel network formation capacity is measured in the tube formation assay.(25,26) However, the relevance of these in vitro assays remains questionable, due to the lack of a functional blood flow, complex ECM, and cells.”
A wearable and stretchable dual-wavelength LED device for home care of chronic infected wounds
Li, M., Wang, C., Yu, Q., Chen, H., Ma, Y., Li, W., Wu, M. X., Yao, M., & Lu, M. (2024) · Nature Communications · doi:10.1038/s41467-024-53579-6 · Cited by 69 · see citing works
“Tube formation assay is an important method for studying angiogenesis in vitro 52 .”
Su, J. L.-S., Satchell, S. C., Wertheim, J. A., & Shah, R. N. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.02.001 · Cited by 69 · see citing works
“Experimental studies involving cell culture on hydrogel substrates were performed in a similar manner as previously-established endothelial cell tube formation assays[31, 32].”
MethodResultDJ-1 promotes angiogenesis and osteogenesis by activating FGF receptor-1 signaling
Kim, J., Shin, H.-I., Cha, S., Lee, C. S., Hong, B. S., Lim, S., Jang, H., Kim, J. J., Yang, Y. R., Kim, Y., et al. (2012) · Nature Communications · doi:10.1038/ncomms2313 · Cited by 66 · see citing works
Zhou, N., Zhao, W., Liu, D., Liang, Y., Fang, W., Li, B., & Chen, Y. (2011) · Microvascular Research · doi:10.1016/j.mvr.2011.06.005 · Cited by 67 · see citing works
A Novel Method for Isolating Individual Cellular Components from the Adult Human Distal Lung
Fujino, N., Kubo, H., Ota, C., Suzuki, T., Suzuki, S. O., Yamada, M., Takahashi, T., He, M. T., SUZUKI, T. A., Kondo, T., et al. (2011) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2011-0172oc · Cited by 66 · see citing works
“A tube formation assay was performed according to previously reported methods, with some modifications (16).”
Methodβ-Caryophyllene Induces Apoptosis and Inhibits Angiogenesis in Colorectal Cancer Models
Dahham, S. S., Tabana, Y., Asif, M., Ahmed, M., Babu, D., Hassan, L. E. A., Ahamed, M. B. K., Sandai, D. A., Barakat, K., Siraki, A. G., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910550 · Cited by 65 · see citing works
“A well-established reported method (endothelial cell tube formation plate system for angiogenesis) was used to analyze the capillary formation ability of HUVECs on Matrigel® matrix [42].”
MethodMesoporous Silica Nanoparticles as an Antitumoral-Angiogenesis Strategy
Setyawati, M. I., & Leong, D. T. (2017) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.6b12524 · Cited by 65 · see citing works
Edman, N., Phal, A., Redler, R. L., Schlichthaerle, T., Srivatsan, S., Ehnes, D., Etemadi, A., An, S. J., Favor, A., Li, Z., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.025 · Cited by 51 · see citing works
“The capacity to assemble into capillary-like tubules is a hallmark phenotype of endothelial cells, 59 and the cells derived via FGFR c-isoform activation demonstrated a robust 2D network formation capacity (measured by numbers of nodes, segments, and meshes in a tube formation assay) (Figures 5F…”
BackgroundAndersson, H., & Brittebo, E. B. (2011) · Archives of Toxicology · doi:10.1007/s00204-011-0766-2 · Cited by 64 · see citing works
“Tube formation assay The endothelial tube formation assay was performed as described by Arnaoutova and co-workers (Arnaoutova and Kleinman 2010).”
EGFR/EGFRvIII Dual-Targeting Peptide-Mediated Drug Delivery for Enhanced Glioma Therapy
Mao, J., Ran, D., Xie, C., Shen, Q., Wang, S., & Lu, W. (2017) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.7b05617 · Cited by 64 · see citing works
Truskey, G. A. (2010) · International Journal of High Throughput Screening · doi:10.2147/ijhts.s13459 · Cited by 64 · see citing works
“In the high-throughput version of these assays, ECs are placed either above a thin gel of collagen I or II 77 or Matrigel, a tumor-derived basement membrane, 78 or in a well placed within the center of gel.”
A perfusable, vascularized kidney organoid-on-chip model
Kroll, K. T., Homan, K. A., Uzel, S. G. M., Mata, M. M., Wolf, K. J., Rubins, J. E., & Lewis, J. A. (2024) · Biofabrication · doi:10.1088/1758-5090/ad5ac0 · Cited by 63 · see citing works
“Endogenous endothelial (CD31 + ) cells are also present at the migrating cell front within the matrix between channels, where both individual cells and more chord-like structures are observed [29, 30].”
PI3K/AKT/PTEN Signaling as a Molecular Target in Leukemia Angiogenesis
Okumura, N., Yoshida, H., Kitagishi, Y., Murakami, M., Nishimura, Y., & Matsuda, S. (2012) · Advances in Hematology · doi:10.1155/2012/843085 · Cited by 62 · see citing works
“Hindawi Publishing Corporation Advances in Hematology Volume 2012, Article ID 843085, 6 pages doi:10.1155/2012/843085 Review Article PI3K/AKT/PTEN Signaling as a Molecular Target in Leukemia Angiogenesis Naoko Okumura, Hitomi Yoshida, Yasuko Kitagishi, Mutsumi Murakami, Yuri Nishimura, and Satoru…”
InfluentialHellevik, T., Pettersen, I., Berg, V., Bruun, J., Bartnes, K., Busund, L., Chalmers, A. J., Bremnes, R. M., & Martínez-Zubiaurre, I. (2013) · Translational Oncology · doi:10.1593/tlo.12349 · Cited by 62 · see citing works
“The formation of capillary-like structures was assessed in Matrigel-coated multiwell plates essentially as described [46].”
Peddibhotla, S. S. D., Brinkmann, B., Kummer, D., Tuncay, H., Nakayama, M., Adams, R. H., Gerke, V., & Ebnet, K. (2013) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-06-0481 · Cited by 62 · see citing works
“In vitro tube formation assay In vitro tube formation assays were performed according to the protocol described by Arnaoutova and Kleinman (2010). Briefly, Cultrex basement membrane extract (BME) with reduced growth factors”
Netrin-4 promotes mural cell adhesion and recruitment to endothelial cells
Lejmi, E., Bouras, I., Camelo, S., Roumieux, M., Minet, N., Déan, C., Merkulova‐Rainon, T., Autret, G., Vayssettes, C., Clémеnt, O., et al. (2014) · Vascular Cell · doi:10.1186/2045-824x-6-1 · Cited by 61 · see citing works
“The in vitro angiogenesis assay was performed according to a previously published protocol [31].”
Editing VEGFR2 Blocks VEGF-Induced Activation of Akt and Tube Formation
Huang, X., Zhou, G., Wu, W., Ma, G., D'Amore, P. A., Mukai, S., & Lei, H. (2017) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.16-20537 · Cited by 61 · see citing works
“Experiments were performed a minimum of three times.(25,33,34)”
- Authors
- Arnaoutova, I., & Kleinman, H. K.
- Affiliations
- Trevigen (US)
- National Institutes of Health (US)
- Corresponding author
- Arnaoutova, Irina
- Kleinman, Hynda K
- ORCID
- Kleinman, Hynda K
- Venue
- Nature Protocols
- Published
- 2010-03-11
- Volume
- 5
- Issue
- 4
- Pages
- 628-635
- ISSN
- 1750-2799 (ISSN-L)
- 1754-2189
- OpenAlex
- W2015186671
- Cited by
- 760
- References
- 35
- Citations by year
- 2026: 29 · 2025: 60 · 2024: 55 · 2023: 54 · 2022: 60 · 2021: 62 · 2020: 57 · 2019: 56 · 2018: 59 · 2017: 66 · 2016: 54 · 2015: 31 · 2014: 41 · 2013: 33 · 2012: 26
- FWCI
- 9.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Protocols (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- in vitro angiogenesis assay, endothelial tube formation, basement membrane extract, capillary-like structures, endothelial cell adhesion, endothelial cell migration, proteolytic activity, endothelial progenitor cells, angiogenesis inhibitors, high-throughput screening
- MeSH terms
- Basement Membrane, Capillaries, Cells, Cultured, Cytological Techniques, Gels, Humans, Neovascularization, Physiologic, Endothelial Cells, In Vitro Techniques
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