{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:55:26Z","timestamp":1792205726092,"version":"4.4.0"},"reference-count":134,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T00:00:00Z","timestamp":1613347200000},"content-version":"vor","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Exp Mol Med"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Blinding eye diseases such as corneal neovascularization, proliferative diabetic retinopathy, and age-related macular degeneration are driven by pathological angiogenesis. In cancer, angiogenesis is key for tumor growth and metastasis. Current antiangiogenic treatments applied clinically interfere with the VEGF signaling pathway\u2014the main angiogenic pathway\u2014to inhibit angiogenesis. These treatments are, however, only partially effective in regressing new pathologic vessels, and the disease relapses following cessation of treatment. Moreover, the relapse of pathological angiogenesis can be rapid, aggressive and more difficult to treat than angiogenesis in the initial phase. The manner in which relapse occurs is poorly understood; however, recent studies have begun to shed light on the mechanisms underlying the revascularization process. Hypotheses have been generated to explain the rapid angiogenic relapse and increased resistance of relapsed disease to treatment. In this context, the present review summarizes knowledge of the various mechanisms of disease relapse gained from different experimental models of pathological angiogenesis. In addition, the basement membrane\u2014a remnant of regressed vessels\u2014is examined in detail to discuss its potential role in disease relapse. Finally, approaches for gaining a better understanding of the relapse process are discussed, including prospects for the management of relapse in the context of disease.<\/jats:p>","DOI":"10.1038\/s12276-021-00566-2","type":"journal-article","created":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T14:09:54Z","timestamp":1613570994000},"page":"189-201","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Relapse of pathological angiogenesis: functional role of the basement membrane and potential treatment strategies"],"prefix":"10.1038","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9645-8942","authenticated-orcid":false,"given":"Anthony","family":"Mukwaya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lasse","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1079-4361","authenticated-orcid":false,"given":"Neil","family":"Lagali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,15]]},"reference":[{"key":"566_CR1","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1358\/dof.1998.023.01.858340","volume":"23","author":"SA Mousa","year":"1998","unstructured":"Mousa, S. A. Mechanisms of angiogenesis in vascular disorders: potential therapeutic targets. Drugs Future 23, 51\u201360 (1998).","journal-title":"Drugs Future"},{"key":"566_CR2","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.ophtha.2012.07.038","volume":"120","author":"JW Miller","year":"2013","unstructured":"Miller, J. W., Le Couter, J., Strauss, E. C. & Ferrara, N. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology 120, 106\u2013114 (2013).","journal-title":"Ophthalmology"},{"key":"566_CR3","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1097\/00003226-198706040-00004","volume":"6","author":"RJ Epstein","year":"1987","unstructured":"Epstein, R. J., Stulting, R. D., Hendricks, R. & Harris, D. M. Corneal neovascularization. Pathogenesis and inhibition. Cornea 6, 250\u2013257 (1987).","journal-title":"Cornea"},{"key":"566_CR4","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1038\/ncb1486","volume":"8","author":"J Gavard","year":"2006","unstructured":"Gavard, J. & Gutkind, J. S. VEGF controls endothelial-cell permeability by promoting the \u03b2-arrestin-dependent endocytosis of VE-cadherin. Nat. Cell Biol. 8, 1223\u20131234 (2006).","journal-title":"Nat. Cell Biol."},{"key":"566_CR5","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1161\/01.ATV.0000209518.58252.17","volume":"26","author":"VW Van Hinsbergh","year":"2006","unstructured":"Van Hinsbergh, V. W., Engelse, M. A. & Quax, P. H. Pericellular proteases in angiogenesis and vasculogenesis. Arterioscler. Thromb. Vasc. Biol. 26, 716\u2013728 (2006).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"566_CR6","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/nrc745","volume":"2","author":"M Egeblad","year":"2002","unstructured":"Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2, 161\u2013174 (2002).","journal-title":"Nat. Rev. Cancer"},{"key":"566_CR7","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1042\/bj2960803","volume":"296","author":"R Hanemaaijer","year":"1993","unstructured":"Hanemaaijer, R., Koolwijk, P., Le Clercq, L., De Vree, W. & Van Hinsbergh, V. Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells. Effects of tumour necrosis factor \u03b1, interleukin 1 and phorbol ester. Biochem. J. 296, 803\u2013809 (1993).","journal-title":"Biochem. J."},{"key":"566_CR8","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1002\/ijc.20945","volume":"115","author":"MM Handsley","year":"2005","unstructured":"Handsley, M. M. & Edwards, D. R. Metalloproteinases and their inhibitors in tumor angiogenesis. Int. J. Cancer 115, 849\u2013860 (2005).","journal-title":"Int. J. Cancer"},{"key":"566_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/gb-2005-6-2-209","volume":"6","author":"DI Holmes","year":"2005","unstructured":"Holmes, D. I. & Zachary, I. The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol. 6, 1\u201310 (2005).","journal-title":"Genome Biol."},{"key":"566_CR10","first-page":"5629","volume":"46","author":"DR Senger","year":"1986","unstructured":"Senger, D. R., Perruzzi, C. A., Feder, J. & Dvorak, H. F. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 46, 5629\u20135632 (1986).","journal-title":"Cancer Res."},{"key":"566_CR11","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1128\/MCB.23.1.14-25.2003","volume":"23","author":"Z-J Liu","year":"2003","unstructured":"Liu, Z.-J. et al. Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol. Cell. Biol. 23, 14\u201325 (2003).","journal-title":"Mol. Cell. Biol."},{"key":"566_CR12","doi-asserted-by":"publisher","first-page":"a006569","DOI":"10.1101\/cshperspect.a006569","volume":"3","author":"R Blanco","year":"2013","unstructured":"Blanco, R. & Gerhardt, H. VEGF and Notch in tip and stalk cell selection. Cold Spring Harb. Perspect. Med. 3, a006569 (2013).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"566_CR13","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1038\/nature05571","volume":"445","author":"M Hellstr\u00f6m","year":"2007","unstructured":"Hellstr\u00f6m, M. et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776\u2013780 (2007).","journal-title":"Nature"},{"key":"566_CR14","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1016\/j.cell.2009.03.025","volume":"137","author":"R Benedito","year":"2009","unstructured":"Benedito, R. et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137, 1124\u20131135 (2009).","journal-title":"Cell"},{"key":"566_CR15","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.cell.2011.08.039","volume":"146","author":"M Potente","year":"2011","unstructured":"Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873\u2013887 (2011).","journal-title":"Cell"},{"key":"566_CR16","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.oret.2017.07.009","volume":"2","author":"SD Adrean","year":"2018","unstructured":"Adrean, S. D., Chaili, S., Grant, S. & Pirouz, A. Recurrence rate of choroidal neovascularization in neovascular age-related macular degeneration managed with a treat\u2013extend\u2013stop protocol. Ophthalmol. Retin. 2, 225\u2013230 (2018).","journal-title":"Ophthalmol. Retin."},{"key":"566_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/ncomms12680","volume":"7","author":"Y Yang","year":"2016","unstructured":"Yang, Y. et al. Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. Nat. Commun. 7, 1\u201313 (2016).","journal-title":"Nat. Commun."},{"key":"566_CR18","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1007\/s10456-019-09679-9","volume":"22","author":"A Mukwaya","year":"2019","unstructured":"Mukwaya, A. et al. Revascularization after angiogenesis inhibition favors new sprouting over abandoned vessel reuse. Angiogenesis 22, 553\u2013567 (2019).","journal-title":"Angiogenesis"},{"key":"566_CR19","doi-asserted-by":"publisher","first-page":"2610","DOI":"10.1172\/JCI24612","volume":"116","author":"MR Mancuso","year":"2006","unstructured":"Mancuso, M. R. et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J. Clin. Investig. 116, 2610\u20132621 (2006).","journal-title":"J. Clin. Investig."},{"key":"566_CR20","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/0092-8674(93)80047-I","volume":"74","author":"RA Lang","year":"1993","unstructured":"Lang, R. A. & Bishop, J. M. Macrophages are required for cell death and tissue remodeling in the developing mouse eye. Cell 74, 453\u2013462 (1993).","journal-title":"Cell"},{"key":"566_CR21","doi-asserted-by":"publisher","first-page":"3929","DOI":"10.1242\/dev.122.12.3929","volume":"122","author":"A Meeson","year":"1996","unstructured":"Meeson, A., Palmer, M., Calfon, M. & Lang, R. A relationship between apoptosis and flow during programmed capillary regression is revealed by vital analysis. Development 122, 3929\u20133938 (1996).","journal-title":"Development"},{"key":"566_CR22","doi-asserted-by":"publisher","first-page":"3395","DOI":"10.1242\/dev.120.12.3395","volume":"120","author":"R Lang","year":"1994","unstructured":"Lang, R., Lustig, M., Francois, F., Sellinger, M. & Plesken, H. Apoptosis during macrophage-dependent ocular tissue remodelling. Development 120, 3395\u20133403 (1994).","journal-title":"Development"},{"key":"566_CR23","doi-asserted-by":"publisher","first-page":"3633","DOI":"10.1242\/dev.124.18.3633","volume":"124","author":"G Diez-Roux","year":"1997","unstructured":"Diez-Roux, G. & Lang, R. A. Macrophages induce apoptosis in normal cells in vivo. Development 124, 3633\u20133638 (1997).","journal-title":"Development"},{"key":"566_CR24","doi-asserted-by":"publisher","first-page":"2141","DOI":"10.1242\/dev.126.10.2141","volume":"126","author":"G Diez-Roux","year":"1999","unstructured":"Diez-Roux, G., Argilla, M., Makarenkova, H., Ko, K. & Lang, R. A. Macrophages kill capillary cells in G1 phase of the cell cycle during programmed vascular regression. Development 126, 2141\u20132147 (1999).","journal-title":"Development"},{"key":"566_CR25","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1253\/circj.CJ-09-0583","volume":"73","author":"J Ando","year":"2009","unstructured":"Ando, J. & Yamamoto, K. Vascular mechanobiology. Circulation J. 73, 1983\u20131992 (2009).","journal-title":"Circulation J."},{"key":"566_CR26","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.biomaterials.2005.07.036","volume":"27","author":"AI Barakat","year":"2006","unstructured":"Barakat, A. I., Lieu, D. K. & Gojova, A. Secrets of the code: do vascular endothelial cells use ion channels to decipher complex flow signals? Biomaterials 27, 671\u2013678 (2006).","journal-title":"Biomaterials"},{"key":"566_CR27","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1161\/01.ATV.6.2.220","volume":"6","author":"MJ Levesque","year":"1986","unstructured":"Levesque, M. J., Liepsch, D., Moravec, S. & Nerem, R. M. Correlation of endothelial cell shape and wall shear stress in a stenosed dog aorta. Arteriosclerosis 6, 220\u2013229 (1986).","journal-title":"Arteriosclerosis"},{"key":"566_CR28","doi-asserted-by":"publisher","first-page":"H983","DOI":"10.1152\/ajpheart.00168.2011","volume":"302","author":"J Zhang","year":"2011","unstructured":"Zhang, J. & Friedman, M. H. The adaptive response of vascular endothelial cells to an acute increase in shear stress magnitude. Am. J. Physiol.\u2014Heart Circulatory Physiol. 302, H983\u2013H991 (2011).","journal-title":"Am. J. Physiol.\u2014Heart Circulatory Physiol."},{"key":"566_CR29","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1115\/1.1486468","volume":"124","author":"BR Blackman","year":"2002","unstructured":"Blackman, B. R., Garc\u0131a-Cardena, G. & Gimbrone, M. A. A new in vitro model to evaluate differential responses of endothelial cells to simulated arterial shear stress waveforms. J. Biomech. Eng. 124, 397\u2013407 (2002).","journal-title":"J. Biomech. Eng."},{"key":"566_CR30","doi-asserted-by":"publisher","first-page":"C621","DOI":"10.1152\/ajpcell.00156.2010","volume":"299","author":"B Melchior","year":"2010","unstructured":"Melchior, B. & Frangos, J. A. Shear-induced endothelial cell-cell junction inclination. Am. J. Physiol.\u2014Cell Physiol. 299, C621\u2013C629 (2010).","journal-title":"Am. J. Physiol.\u2014Cell Physiol."},{"key":"566_CR31","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1113\/jphysiol.2004.075218","volume":"561","author":"X Lu","year":"2004","unstructured":"Lu, X. & Kassab, G. Nitric oxide is significantly reduced in ex vivo porcine arteries during reverse flow because of increased superoxide production. J. Physiol. 561, 575\u2013582 (2004).","journal-title":"J. Physiol."},{"key":"566_CR32","doi-asserted-by":"publisher","first-page":"H1077","DOI":"10.1152\/ajpheart.00956.2012","volume":"304","author":"RH Adamson","year":"2013","unstructured":"Adamson, R. H. et al. Microvascular permeability to water is independent of shear stress, but dependent on flow direction. Am. J. Physiol.-Heart Circ. Physiol. 304, H1077\u2013H1084 (2013).","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"566_CR33","doi-asserted-by":"publisher","first-page":"2130","DOI":"10.1161\/ATVBAHA.113.301826","volume":"33","author":"C Wang","year":"2013","unstructured":"Wang, C., Baker, B. M., Chen, C. S. & Schwartz, M. A. Endothelial cell sensing of flow direction. Arterioscler. Thromb. Vasc. Biol. 33, 2130\u20132136 (2013).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"566_CR34","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1006\/bbrc.2000.3873","volume":"278","author":"B Bartling","year":"2000","unstructured":"Bartling, B. et al. Shear stress-dependent expression of apoptosis-regulating genes in endothelial cells. Biochem. Biophys. Res. Commun. 278, 740\u2013746 (2000).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"566_CR35","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1161\/01.RES.83.3.334","volume":"83","author":"S Dimmeler","year":"1998","unstructured":"Dimmeler, S., Assmus, B., Hermann, C., Haendeler, J. & Zeiher, A. M. Fluid shear stress stimulates phosphorylation of Akt in human endothelial cells: involvement in suppression of apoptosis. Circ. Res. 83, 334\u2013341 (1998).","journal-title":"Circ. Res."},{"key":"566_CR36","first-page":"313","volume":"33","author":"J Zhang","year":"2013","unstructured":"Zhang, J. et al. Low shear stress induces human vascular endothelial cell apoptosis by activating Akt signal and increasing reactive oxygen species. Nan Fang. Yi Ke Da Xue Xue Bao 33, 313\u2013317 (2013).","journal-title":"Nan Fang. Yi Ke Da Xue Xue Bao"},{"key":"566_CR37","first-page":"689.614","volume":"31","author":"Y-L Hu","year":"2017","unstructured":"Hu, Y.-L., Hur, S. S., Lei, L., Wang, Y. & Chien, S. Shear stress induces apoptosis via cytochrome c release from dynamic mitochondria in endothelial cells. FASEB J. 31, 689.614\u2013689.614 (2017).","journal-title":"FASEB J."},{"key":"566_CR38","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1093\/cvr\/cvq396","volume":"90","author":"JL James","year":"2010","unstructured":"James, J. L., Whitley, G. S. & Cartwright, J. E. Shear stress and spiral artery remodelling: the effects of low shear stress on trophoblast-induced endothelial cell apoptosis. Cardiovasc. Res. 90, 130\u2013139 (2010).","journal-title":"Cardiovasc. Res."},{"key":"566_CR39","first-page":"964","volume":"41","author":"S Kim","year":"2018","unstructured":"Kim, S. & Woo, C.-H. Laminar flow inhibits ER stress-induced endothelial apoptosis through PI3K\/Akt-dependent signaling pathway. Mol. Cells 41, 964 (2018).","journal-title":"Mol. Cells"},{"key":"566_CR40","doi-asserted-by":"crossref","first-page":"4235","DOI":"10.1172\/JCI143197","volume":"130","author":"ZL Grant","year":"2020","unstructured":"Grant, Z. L. et al. Blocking endothelial apoptosis revascularises the retina in a model of ischemic retinopathy. J Clin. Invest. 130, 4235\u20134251 (2020).","journal-title":"J Clin. Invest."},{"key":"566_CR41","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1161\/ATVBAHA.119.313536","volume":"40","author":"GM Koller","year":"2020","unstructured":"Koller, G. M. et al. Proinflammatory mediators, IL (Interleukin)-1\u03b2, TNF (Tumor Necrosis Factor) \u03b1, and thrombin directly induce capillary tube regression. Arterioscler. Thromb. Vasc. Biol. 40, 365\u2013377 (2020).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"566_CR42","doi-asserted-by":"publisher","first-page":"2002","DOI":"10.1016\/j.ophtha.2006.05.070","volume":"113","author":"AA Moshfeghi","year":"2006","unstructured":"Moshfeghi, A. A. et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four\u2013week results of an uncontrolled open-label clinical study. Ophthalmology 113, 2002\u20132011. e2002 (2006).","journal-title":"Ophthalmology"},{"key":"566_CR43","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/nrd1381","volume":"3","author":"N Ferrara","year":"2004","unstructured":"Ferrara, N., Hillan, K. J., Gerber, H.-P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov. 3, 391 (2004).","journal-title":"Nat. Rev. Drug Discov."},{"key":"566_CR44","doi-asserted-by":"publisher","first-page":"2805","DOI":"10.1056\/NEJMoa042760","volume":"351","author":"ES Gragoudas","year":"2004","unstructured":"Gragoudas, E. S., Adamis, A. P., Cunningham, Jr,E. T., Feinsod, M. & Guyer, D. R. Pegaptanib for neovascular age-related macular degeneration. N. Engl. J. Med. 351, 2805\u20132816 (2004).","journal-title":"N. Engl. J. Med."},{"key":"566_CR45","first-page":"4593","volume":"57","author":"LG Presta","year":"1997","unstructured":"Presta, L. G. et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 57, 4593\u20134599 (1997).","journal-title":"Cancer Res."},{"key":"566_CR46","doi-asserted-by":"publisher","first-page":"331","DOI":"10.3928\/1542-8877-20050701-14","volume":"36","author":"PJ Rosenfeld","year":"2005","unstructured":"Rosenfeld, P. J., Moshfeghi, A. A. & Puliafito, C. A. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin\u00ae) for neovascular age-related macular degeneration. Ophthalmic Surg., Lasers Imaging Retin. 36, 331\u2013335 (2005).","journal-title":"Ophthalmic Surg., Lasers Imaging Retin."},{"key":"566_CR47","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1056\/NEJMoa062655","volume":"355","author":"DM Brown","year":"2006","unstructured":"Brown, D. M. et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N. Engl. J. Med. 355, 1432\u20131444 (2006).","journal-title":"N. Engl. J. Med."},{"key":"566_CR48","doi-asserted-by":"publisher","first-page":"1897","DOI":"10.1056\/NEJMoa1102673","volume":"364","author":"CR Group","year":"2011","unstructured":"Group, C. R. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 364, 1897\u20131908 (2011).","journal-title":"N. Engl. J. Med."},{"key":"566_CR49","doi-asserted-by":"publisher","first-page":"11393","DOI":"10.1073\/pnas.172398299","volume":"99","author":"J Holash","year":"2002","unstructured":"Holash, J. et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc. Natl Acad. Sci. 99, 11393\u201311398 (2002).","journal-title":"Proc. Natl Acad. Sci."},{"key":"566_CR50","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0801-5","volume":"17","author":"Q Jiao","year":"2018","unstructured":"Jiao, Q. et al. Advances in studies of tyrosine kinase inhibitors and their acquired resistance. Mol. Cancer 17, 36 (2018).","journal-title":"Mol. Cancer"},{"key":"566_CR51","doi-asserted-by":"crossref","unstructured":"Imbulgoda, A., Heng, D. Y. & Kollmannsberger, C. Sunitinib in the treatment of advanced solid tumors. in Small Molecules in Oncology 165-184 (Springer, 2014).","DOI":"10.1007\/978-3-642-54490-3_9"},{"key":"566_CR52","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.ccr.2009.01.021","volume":"15","author":"JM Ebos","year":"2009","unstructured":"Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232\u2013239 (2009).","journal-title":"Cancer Cell"},{"key":"566_CR53","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.ccr.2009.01.027","volume":"15","author":"M P\u00e0ez-Ribes","year":"2009","unstructured":"P\u00e0ez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220\u2013231 (2009).","journal-title":"Cancer Cell"},{"key":"566_CR54","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1038\/aps.2017.5","volume":"38","author":"Y-j Zhu","year":"2017","unstructured":"Zhu, Y.-j, Zheng, B., Wang, H.-y & Chen, L. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharm. Sin. 38, 614\u2013622 (2017).","journal-title":"Acta Pharm. Sin."},{"key":"566_CR55","doi-asserted-by":"publisher","first-page":"7271","DOI":"10.1158\/1078-0432.CCR-06-1249","volume":"12","author":"RC Kane","year":"2006","unstructured":"Kane, R. C. et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin. Cancer Res. 12, 7271\u20137278 (2006).","journal-title":"Clin. Cancer Res."},{"key":"566_CR56","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.2147\/DDDT.S115121","volume":"10","author":"S Yang","year":"2016","unstructured":"Yang, S., Zhao, J. & Sun, X. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review. Drug Des. Dev. Ther. 10, 1857 (2016).","journal-title":"Drug Des. Dev. Ther."},{"key":"566_CR57","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/1756-9966-32-92","volume":"32","author":"G Tonini","year":"2013","unstructured":"Tonini, G., Imperatori, M., Vincenzi, B., Frezza, A. M. & Santini, D. Rechallenge therapy and treatment holiday: different strategies in management of metastatic colorectal cancer. J. Exp. Clin. Cancer Res. 32, 92 (2013).","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"566_CR58","doi-asserted-by":"publisher","first-page":"2303","DOI":"10.1016\/j.ophtha.2015.06.053","volume":"122","author":"Y Kuroda","year":"2015","unstructured":"Kuroda, Y. et al. Factors associated with recurrence of age-related macular degeneration after anti-vascular endothelial growth factor treatment: a retrospective cohort study. Ophthalmology 122, 2303\u20132310 (2015).","journal-title":"Ophthalmology"},{"key":"566_CR59","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12680","volume":"7","author":"Y Yang","year":"2016","unstructured":"Yang, Y. et al. Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. Nat. Commun. 7, 12680 (2016).","journal-title":"Nat. Commun."},{"key":"566_CR60","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1016\/S0140-6736(12)60282-7","volume":"379","author":"LS Lim","year":"2012","unstructured":"Lim, L. S., Mitchell, P., Seddon, J. M., Holz, F. G. & Wong, T. Y. Age-related macular degeneration. Lancet 379, 1728\u20131738 (2012).","journal-title":"Lancet"},{"key":"566_CR61","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.mam.2012.04.005","volume":"33","author":"I Bhutto","year":"2012","unstructured":"Bhutto, I. & Lutty, G. Understanding age-related macular degeneration (AMD): relationships between the photoreceptor\/retinal pigment epithelium\/Bruch\u2019s membrane\/choriocapillaris complex. Mol. Asp. Med. 33, 295\u2013317 (2012).","journal-title":"Mol. Asp. Med."},{"key":"566_CR62","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1097\/00006982-200312000-00001","volume":"23","author":"JDM Gass","year":"2003","unstructured":"Gass, J. D. M., Agarwal, A., Lavina, A. M. & Tawansy, K. A. Focal inner retinal hemorrhages in patients with drusen: an early sign of occult choroidal neovascularization and chorioretinal anastomosis. Retina 23, 741\u2013751 (2003).","journal-title":"Retina"},{"key":"566_CR63","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1097\/ICU.0000000000000050","volume":"25","author":"A Rasmussen","year":"2014","unstructured":"Rasmussen, A. & Sander, B. Long-term longitudinal study of patients treated with ranibizumab for neovascular age-related macular degeneration. Curr. Opin. Ophthalmol. 25, 158\u2013163 (2014).","journal-title":"Curr. Opin. Ophthalmol."},{"key":"566_CR64","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.ophtha.2015.10.047","volume":"123","author":"RS Feder","year":"2016","unstructured":"Feder, R. S. et al. Comprehensive adult medical eye evaluation Preferred Practice Pattern\u00ae guidelines. Ophthalmology 123, 209\u2013236 (2016).","journal-title":"Ophthalmology"},{"key":"566_CR65","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2017-018289","volume":"7","author":"W Hollingworth","year":"2017","unstructured":"Hollingworth, W., Jones, T., Reeves, B. C. & Peto, T. A longitudinal study to assess the frequency and cost of antivascular endothelial therapy, and inequalities in access, in England between 2005 and 2015. BMJ Open 7, e018289 (2017).","journal-title":"BMJ Open"},{"key":"566_CR66","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1016\/j.oret.2017.12.006","volume":"2","author":"S Patel","year":"2018","unstructured":"Patel, S. Medicare spending on anti\u2013vascular endothelial growth factor medications. Ophthalmol. Retin. 2, 785\u2013791 (2018).","journal-title":"Ophthalmol. Retin."},{"key":"566_CR67","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.ophtha.2012.07.026","volume":"120","author":"R Silva","year":"2013","unstructured":"Silva, R. et al. The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related macular degeneration. Ophthalmology 120, 130\u2013139 (2013).","journal-title":"Ophthalmology"},{"key":"566_CR68","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1038\/nrc2442","volume":"8","author":"G Bergers","year":"2008","unstructured":"Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592 (2008).","journal-title":"Nat. Rev. Cancer"},{"key":"566_CR69","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep27082","volume":"6","author":"JJ Chan","year":"2016","unstructured":"Chan, J. J. et al. Risk of recurrence of retinopathy of prematurity after initial intravitreal ranibizumab therapy. Sci. Rep. 6, 1\u20137 (2016).","journal-title":"Sci. Rep."},{"key":"566_CR70","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1097\/IAE.0000000000000578","volume":"35","author":"RK Wong","year":"2015","unstructured":"Wong, R. K., Hubschman, S. & Tsui, I. Reactivation of retinopathy of prematurity after ranibizumab treatment. Retina 35, 675\u2013680 (2015).","journal-title":"Retina"},{"key":"566_CR71","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1001\/archophthalmol.2012.592","volume":"130","author":"J Hu","year":"2012","unstructured":"Hu, J. et al. Reactivation of retinopathy of prematurity after bevacizumab injection. Arch. Ophthalmol. 130, 1000\u20131006 (2012).","journal-title":"Arch. Ophthalmol."},{"key":"566_CR72","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1097\/IAE.0b013e318285cc24","volume":"33","author":"HM Kang","year":"2013","unstructured":"Kang, H. M. & Koh, H. J. Ocular risk factors for recurrence of myopic choroidal neovascularization: long-term follow-up study. Retina 33, 1613\u20131622 (2013).","journal-title":"Retina"},{"key":"566_CR73","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1136\/bjo.2006.110239","volume":"91","author":"MJ Potter","year":"2007","unstructured":"Potter, M. J. & Szabo, S. M. Recurrence of choroidal neovascularization after photodynamic therapy in patients with age-related macular degeneration. Br. J. Ophthalmol. 91, 753\u2013756 (2007).","journal-title":"Br. J. Ophthalmol."},{"key":"566_CR74","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/S0039-6257(98)00035-6","volume":"43","author":"P Lee","year":"1998","unstructured":"Lee, P., Wang, C. C. & Adamis, A. P. Ocular neovascularization: an epidemiologic review. Surv. Ophthalmol. 43, 245\u2013269 (1998).","journal-title":"Surv. Ophthalmol."},{"key":"566_CR75","doi-asserted-by":"publisher","first-page":"1659","DOI":"10.1167\/iovs.08-1997","volume":"50","author":"W-L Chen","year":"2009","unstructured":"Chen, W.-L. et al. Subconjunctival injection of bevacizumab (avastin) on corneal neovascularization in different rabbit models of corneal angiogenesis. Investig. Ophthalmol. Vis. Sci. 50, 1659\u20131665 (2009).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"566_CR76","doi-asserted-by":"publisher","first-page":"6277","DOI":"10.1167\/iovs.09-4571","volume":"51","author":"C-T Lin","year":"2010","unstructured":"Lin, C.-T. et al. The different effects of early and late bevacizumab (Avastin) injection on inhibiting corneal neovascularization and conjunctivalization in rabbit limbal insufficiency. Investig. Ophthalmol. Vis. Sci. 51, 6277\u20136285 (2010).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"566_CR77","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.1097\/ICO.0b013e31825ec407","volume":"32","author":"H-S Chu","year":"2013","unstructured":"Chu, H.-S., Chen, T.-C., Hu, F.-R. & Chen, W.-L. Recurrence of corneal neovascularization associated with lipid deposition after subconjunctival injection of bevacizumab. Cornea 32, 1446\u20131453 (2013).","journal-title":"Cornea"},{"key":"566_CR78","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.exer.2014.06.006","volume":"125","author":"P Mirabelli","year":"2014","unstructured":"Mirabelli, P., Peebo, B. B., Xeroudaki, M., Koulikovska, M. & Lagali, N. Early effects of dexamethasone and anti-VEGF therapy in an inflammatory corneal neovascularization model. Exp. Eye Res. 125, 118\u2013127 (2014).","journal-title":"Exp. Eye Res."},{"key":"566_CR79","doi-asserted-by":"publisher","first-page":"2990","DOI":"10.1167\/iovs.19-27591","volume":"60","author":"A Mukwaya","year":"2019","unstructured":"Mukwaya, A. et al. Repeat corneal neovascularization is characterized by more aggressive inflammation and vessel invasion than in the initial phase. Investig. Ophthalmol. Vis. Sci. 60, 2990\u20133001 (2019).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"566_CR80","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1007\/s11060-010-0121-0","volume":"99","author":"RM Zuniga","year":"2010","unstructured":"Zuniga, R. M. et al. Rebound tumour progression after the cessation of bevacizumab therapy in patients with recurrent high-grade glioma. J. Neuro-Oncol. 99, 237\u2013242 (2010).","journal-title":"J. Neuro-Oncol."},{"key":"566_CR81","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1097\/CAD.0000000000000542","volume":"28","author":"S Oumrani","year":"2017","unstructured":"Oumrani, S. et al. Tumour growth increased following antiangiogenic interruption: the challenge of tumour evaluation. Anti-Cancer Drugs 28, 1062\u20131065 (2017).","journal-title":"Anti-Cancer Drugs"},{"key":"566_CR82","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1172\/JCI44562","volume":"121","author":"AF Welford","year":"2011","unstructured":"Welford, A. F. et al. TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. J. Clin. Investig. 121, 1969\u20131973 (2011).","journal-title":"J. Clin. Investig."},{"key":"566_CR83","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1016\/S0002-9440(10)65005-5","volume":"156","author":"S Kim","year":"2000","unstructured":"Kim, S., Bell, K., Mousa, S. A. & Varner, J. A. Regulation of angiogenesis in vivo by ligation of integrin \u03b15\u03b21 with the central cell-binding domain of fibronectin. Am. J. Pathol. 156, 1345\u20131362 (2000).","journal-title":"Am. J. Pathol."},{"key":"566_CR84","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1126\/science.1176009","volume":"326","author":"RO Hynes","year":"2009","unstructured":"Hynes, R. O. The extracellular matrix: not just pretty fibrils. Science 326, 1216\u20131219 (2009).","journal-title":"Science"},{"key":"566_CR85","doi-asserted-by":"crossref","unstructured":"Varner, J. The role of vascular cell integrins \u03b1v\u00df3 and \u03b1v\u00df5 in angiogenesis. in Regulation of Angiogenesis 361-390 (Springer, 1997).","DOI":"10.1007\/978-3-0348-9006-9_15"},{"key":"566_CR86","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1007\/s10456-011-9223-3","volume":"14","author":"BB Peebo","year":"2011","unstructured":"Peebo, B. B., Fagerholm, P., Traneus-R\u00f6ckert, C. & Lagali, N. Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model. Angiogenesis 14, 393 (2011).","journal-title":"Angiogenesis"},{"key":"566_CR87","doi-asserted-by":"publisher","DOI":"10.1038\/srep32137","volume":"6","author":"A Mukwaya","year":"2016","unstructured":"Mukwaya, A. et al. Factors regulating capillary remodeling in a reversible model of inflammatory corneal angiogenesis. Sci. Rep. 6, 32137 (2016).","journal-title":"Sci. Rep."},{"key":"566_CR88","doi-asserted-by":"publisher","first-page":"2340","DOI":"10.1016\/j.ajpath.2019.07.009","volume":"189","author":"TE Zhou","year":"2019","unstructured":"Zhou, T. E. et al. The inability of the choroid to revascularize in oxygen-induced retinopathy results from increased p53\/miR-Let-7b activity. Am. J. Pathol. 189, 2340\u20132356 (2019).","journal-title":"Am. J. Pathol."},{"key":"566_CR89","doi-asserted-by":"crossref","unstructured":"Lumbroso, B., et al. Optical coherence tomography angiography study of choroidal neovascularization early response after treatment. In OCT Angiography in Retinal and Macular Diseases, Vol. 56 77-85 (Karger Publishers, 2016).","DOI":"10.1159\/000442782"},{"key":"566_CR90","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1097\/IAE.0000000000001447","volume":"37","author":"A Miere","year":"2017","unstructured":"Miere, A. et al. Optical coherence tomography angiography changes in early type 3 neovascularization after anti-vascular endothelial growth factor treatment. Retina 37, 1873\u20131879 (2017).","journal-title":"Retina"},{"key":"566_CR91","doi-asserted-by":"publisher","first-page":"a004911","DOI":"10.1101\/cshperspect.a004911","volume":"3","author":"PD Yurchenco","year":"2011","unstructured":"Yurchenco, P. D. Basement membranes: cell scaffoldings and signaling platforms. Cold Spring Harb. Perspect. Biol. 3, a004911 (2011).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"566_CR92","first-page":"457","volume":"130","author":"W Bowman","year":"1840","unstructured":"Bowman, W. XXI. On the minute structure and movements voluntary muscle. Philos. Trans. R Soc. Lond. 130, 457\u2013501 (1840).","journal-title":"Philos. Trans. R Soc. Lond."},{"key":"566_CR93","doi-asserted-by":"publisher","first-page":"93","DOI":"10.3109\/10409239209082560","volume":"27","author":"M Paulsson","year":"1992","unstructured":"Paulsson, M. Basement membrane proteins: structure, assembly, and cellular interactions. Crit. Rev. Biochem. Mol. Biol. 27, 93\u2013127 (1992).","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"566_CR94","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1002\/1097-0029(20001101)51:3<214::AID-JEMT2>3.0.CO;2-J","volume":"51","author":"P Tunggal","year":"2000","unstructured":"Tunggal, P., Smyth, N., Paulsson, M. & Ott, M. C. Laminins: structure and genetic regulation. Microsc. Res. Technol. 51, 214\u2013227 (2000).","journal-title":"Microsc. Res. Technol."},{"key":"566_CR95","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/j.cell.2005.03.031","volume":"121","author":"DR Sherwood","year":"2005","unstructured":"Sherwood, D. R., Butler, J. A., Kramer, J. M. & Sternberg, P. W. FOS-1 promotes basement-membrane removal during anchor-cell invasion in C. elegans. Cell 121, 951\u2013962 (2005).","journal-title":"Cell"},{"key":"566_CR96","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/346425a0","volume":"346","author":"TA Springer","year":"1990","unstructured":"Springer, T. A. Adhesion receptors of the immune system. Nature 346, 425\u2013434 (1990).","journal-title":"Nature"},{"key":"566_CR97","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1172\/JCI113992","volume":"83","author":"AR Huber","year":"1989","unstructured":"Huber, A. R. & Weiss, S. J. Disruption of the subendothelial basement membrane during neutrophil diapedesis in an in vitro construct of a blood vessel wall. J. Clin. Investig. 83, 1122\u20131136 (1989).","journal-title":"J. Clin. Investig."},{"key":"566_CR98","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1007\/BF00437470","volume":"15","author":"I Vlodavsky","year":"1996","unstructured":"Vlodavsky, I., Miao, H.-Q., Medalion, B., Danagher, P. & Ron, D. Involvement of heparan sulfate and related molecules in sequestration and growth promoting activity of fibroblast growth factor. Cancer Metastasis Rev. 15, 177\u2013186 (1996).","journal-title":"Cancer Metastasis Rev."},{"key":"566_CR99","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0014-4827(92)90397-Q","volume":"202","author":"S Vukicevic","year":"1992","unstructured":"Vukicevic, S. et al. Identification of multiple active growth factors in basement membrane Matrigel suggests caution in interpretation of cellular activity related to extracellular matrix components. Exp. Cell Res. 202, 1\u20138 (1992).","journal-title":"Exp. Cell Res."},{"key":"566_CR100","first-page":"393","volume":"130","author":"J Folkman","year":"1988","unstructured":"Folkman, J. et al. A heparin-binding angiogenic protein-basic fibroblast growth factor-is stored within basement membrane. Am. J. Pathol. 130, 393 (1988).","journal-title":"Am. J. Pathol."},{"key":"566_CR101","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1247\/csf.27.9","volume":"27","author":"Y Tomono","year":"2002","unstructured":"Tomono, Y. et al. Epitope-defined monoclonal antibodies against multiplexin collagens demonstrate that type XV and XVIII collagens are expressed in specialized basement membranes. Cell Struct. Funct. 27, 9\u201320 (2002).","journal-title":"Cell Struct. Funct."},{"key":"566_CR102","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/0014-5793(81)81012-5","volume":"125","author":"K K\u00fchn","year":"1981","unstructured":"K\u00fchn, K. et al. Macromolecular structure of basement membrane collagens: Identification of 7 S collagen as a crosslinking domain of type IV collagen. FEBS Lett. 125, 123\u2013128 (1981).","journal-title":"FEBS Lett."},{"key":"566_CR103","first-page":"1500","volume":"147","author":"S Kivirikko","year":"1995","unstructured":"Kivirikko, S., Saarela, J., Myers, J. C., Autio-Harmainen, H. & Pihlajaniemi, T. Distribution of type XV collagen transcripts in human tissue and their production by muscle cells and fibroblasts. Am. J. Pathol. 147, 1500 (1995).","journal-title":"Am. J. Pathol."},{"key":"566_CR104","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1007\/s004410050719","volume":"286","author":"JC Myers","year":"1996","unstructured":"Myers, J. C., Dion, A. S., Abraham, V., Amenta, P. S. & Type, X. V. collagen exhibits a widespread distribution in human tissues but a distinct localization in basement membrane zones. Cell Tissue Res. 286, 493\u2013505 (1996).","journal-title":"Cell Tissue Res."},{"key":"566_CR105","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/S0945-053X(01)00187-1","volume":"21","author":"A Muona","year":"2002","unstructured":"Muona, A., Eklund, L., V\u00e4is\u00e4nen, T. & Pihlajaniemi, T. Developmentally regulated expression of type XV collagen correlates with abnormalities in Col15a1\u2212\/\u2212 mice. Matrix Biol. 21, 89\u2013102 (2002).","journal-title":"Matrix Biol."},{"key":"566_CR106","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1073\/pnas.98.3.1194","volume":"98","author":"L Eklund","year":"2001","unstructured":"Eklund, L. et al. Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice. Proc. Natl Acad. Sci. 98, 1194\u20131199 (2001).","journal-title":"Proc. Natl Acad. Sci."},{"key":"566_CR107","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1006\/bbrc.1999.0248","volume":"255","author":"R Ramchandran","year":"1999","unstructured":"Ramchandran, R. et al. Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem. Biophys. Res. Commun. 255, 735\u2013739 (1999).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"566_CR108","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.bbapap.2004.10.013","volume":"1747","author":"H John","year":"2005","unstructured":"John, H., Radtke, K., St\u00e4ndker, L. & Forssmann, W.-G. Identification and characterization of novel endogenous proteolytic forms of the human angiogenesis inhibitors restin and endostatin. Biochim. Biophys. Acta (BBA)\u2014Proteins Proteom. 1747, 161\u2013170 (2005).","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Proteins Proteom."},{"key":"566_CR109","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/S0092-8674(00)81848-6","volume":"88","author":"MS O\u2019Reilly","year":"1997","unstructured":"O\u2019Reilly, M. S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277\u2013285 (1997).","journal-title":"Cell"},{"key":"566_CR110","doi-asserted-by":"publisher","first-page":"11721","DOI":"10.1074\/jbc.274.17.11721","volume":"274","author":"M Dhanabal","year":"1999","unstructured":"Dhanabal, M. et al. Endostatin induces endothelial cell apoptosis. J. Biol. Chem. 274, 11721\u201311726 (1999).","journal-title":"J. Biol. Chem."},{"key":"566_CR111","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1006\/mthe.2002.0590","volume":"5","author":"G Yin","year":"2002","unstructured":"Yin, G. et al. Endostatin gene transfer inhibits joint angiogenesis and pannus formation in inflammatory arthritis. Mol. Ther. 5, 547\u2013554 (2002).","journal-title":"Mol. Ther."},{"key":"566_CR112","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1006\/mthe.2000.0243","volume":"3","author":"FA Scappaticci","year":"2001","unstructured":"Scappaticci, F. A. et al. Combination angiostatin and endostatin gene transfer induces synergistic antiangiogenic activity in vitro and antitumor efficacy in leukemia and solid tumors in mice. Mol. Ther. 3, 186\u2013196 (2001).","journal-title":"Mol. Ther."},{"key":"566_CR113","doi-asserted-by":"publisher","first-page":"3403","DOI":"10.1182\/blood.V95.11.3403","volume":"95","author":"J Dixelius","year":"2000","unstructured":"Dixelius, J. et al. Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood 95, 3403\u20133411 (2000).","journal-title":"Blood"},{"key":"566_CR114","doi-asserted-by":"publisher","first-page":"30716","DOI":"10.1074\/jbc.M004569200","volume":"275","author":"A Boutaud","year":"2000","unstructured":"Boutaud, A. et al. Type IV collagen of the glomerular basement membrane evidence that the chain specificity of network assembly is encoded by the noncollagenous nc1 domains. J. Biol. Chem. 275, 30716\u201330724 (2000).","journal-title":"J. Biol. Chem."},{"key":"566_CR115","first-page":"78","volume":"128","author":"R Nicosia","year":"1987","unstructured":"Nicosia, R. & Madri, J. The microvascular extracellular matrix. Developmental changes during angiogenesis in the aortic ring-plasma clot model. Am. J. Pathol. 128, 78 (1987).","journal-title":"Am. J. Pathol."},{"key":"566_CR116","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1290\/1071-2690(2000)036<0336:TICMAA>2.0.CO;2","volume":"36","author":"E Bonanno","year":"2000","unstructured":"Bonanno, E., Iurlaro, M., Madri, J. A. & Nicosia, R. F. Type IV collagen modulates angiogenesis and neovessel survival in the rat aorta model. Vitr. Cell. Dev. Biol.\u2014Anim. 36, 336\u2013340 (2000).","journal-title":"Vitr. Cell. Dev. Biol.\u2014Anim."},{"key":"566_CR117","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1083\/jcb.107.4.1589","volume":"107","author":"Y Kubota","year":"1988","unstructured":"Kubota, Y., Kleinman, H. K., Martin, G. R. & Lawley, T. J. Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures. J. Cell Biol. 107, 1589\u20131598 (1988).","journal-title":"J. Cell Biol."},{"key":"566_CR118","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1083\/jcb.97.1.153","volume":"97","author":"JA Madri","year":"1983","unstructured":"Madri, J. A. & Williams, S. K. Capillary endothelial cell cultures: phenotypic modulation by matrix components. J. Cell Biol. 97, 153\u2013165 (1983).","journal-title":"J. Cell Biol."},{"key":"566_CR119","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1006\/dbio.1994.1191","volume":"164","author":"RF Nicosia","year":"1994","unstructured":"Nicosia, R. F., Bonanno, E., Smith, M. & Yurchenco, P. Modulation of angiogenesis in vitro by laminin-entactin complex. Dev. Biol. 164, 197\u2013206 (1994).","journal-title":"Dev. Biol."},{"key":"566_CR120","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1002\/ijc.26353","volume":"131","author":"J Hwang\u2010Bo","year":"2012","unstructured":"Hwang\u2010Bo, J., Yoo, K. H., Park, J. H., Jeong, H. S. & Chung, I. S. Recombinant canstatin inhibits angiopoietin\u20101\u2010induced angiogenesis and lymphangiogenesis. Int. J. Cancer 131, 298\u2013309 (2012).","journal-title":"Int. J. Cancer"},{"key":"566_CR121","doi-asserted-by":"publisher","first-page":"2589","DOI":"10.1016\/j.bbagen.2013.12.029","volume":"1840","author":"JC Monboisse","year":"2014","unstructured":"Monboisse, J. C., Oudart, J. B., Ramont, L., Brassart-Pasco, S. & Maquart, F. X. Matrikines from basement membrane collagens: a new anti-cancer strategy. Biochim. Biophys. Acta (BBA)\u2014Gen. Subj. 1840, 2589\u20132598 (2014).","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Gen. Subj."},{"key":"566_CR122","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.mvr.2007.05.005","volume":"74","author":"TM Mundel","year":"2007","unstructured":"Mundel, T. M. & Kalluri, R. Type IV collagen-derived angiogenesis inhibitors. Microvasc. Res. 74, 85\u201389 (2007).","journal-title":"Microvasc. Res."},{"key":"566_CR123","doi-asserted-by":"publisher","first-page":"4353","DOI":"10.1158\/0008-5472.CAN-04-3536","volume":"65","author":"C Magnon","year":"2005","unstructured":"Magnon, C. et al. Canstatin acts on endothelial and tumor cells via mitochondrial damage initiated through interaction with \u03b1v\u03b23 and \u03b1v\u03b25 integrins. Cancer Res. 65, 4353\u20134361 (2005).","journal-title":"Cancer Res."},{"key":"566_CR124","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20140012","volume":"34","author":"Y-N Xing","year":"2014","unstructured":"Xing, Y.-N., Deng, P. & Xu, H.-M. Canstatin induces apoptosis in gastric cancer xenograft growth in mice through the mitochondrial apoptotic pathway. Biosci. Rep. 34, e00106 (2014).","journal-title":"Biosci. Rep."},{"key":"566_CR125","doi-asserted-by":"publisher","first-page":"1689","DOI":"10.1159\/000373982","volume":"35","author":"H Cai","year":"2015","unstructured":"Cai, H. et al. Roundabout4 suppresses glioma-induced endothelial cell proliferation, migration and tube formation in vitro by inhibiting VEGR2-mediated PI3K\/AKT and FAK signaling pathways. Cell. Physiol. Biochem. 35, 1689\u20131705 (2015).","journal-title":"Cell. Physiol. Biochem."},{"key":"566_CR126","doi-asserted-by":"publisher","first-page":"37632","DOI":"10.1074\/jbc.M307339200","volume":"278","author":"DJ Panka","year":"2003","unstructured":"Panka, D. J. & Mier, J. W. Canstatin inhibits Akt activation and induces Fas-dependent apoptosis in endothelial cells. J. Biol. Chem. 278, 37632\u201337636 (2003).","journal-title":"J. Biol. Chem."},{"key":"566_CR127","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.2337\/diabetes.53.7.1831","volume":"53","author":"Y Yamamoto","year":"2004","unstructured":"Yamamoto, Y. et al. Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. Diabetes 53, 1831\u20131840 (2004).","journal-title":"Diabetes"},{"key":"566_CR128","first-page":"1794","volume":"52","author":"S Akulapalli","year":"2011","unstructured":"Akulapalli, S., Gunda, V., Laknaur, A. & Shekhar, B. C. Mechanism of regulation of laser induced choroidal neovascularisation by tumstatin. Investig. Ophthalmol. Vis. Sci. 52, 1794\u20131794 (2011).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"566_CR129","doi-asserted-by":"publisher","first-page":"4766","DOI":"10.1073\/pnas.0730882100","volume":"100","author":"A Sudhakar","year":"2003","unstructured":"Sudhakar, A. et al. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by \u03b1v\u03b23 and \u03b15\u03b21 integrins. Proc. Natl Acad. Sci. 100, 4766\u20134771 (2003).","journal-title":"Proc. Natl Acad. Sci."},{"key":"566_CR130","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/S1535-6108(03)00133-8","volume":"3","author":"Y Hamano","year":"2003","unstructured":"Hamano, Y. et al. Physiological levels of tumstatin, a fragment of collagen IV \u03b13 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via \u03b1V\u03b23 integrin. Cancer Cell 3, 589\u2013601 (2003).","journal-title":"Cancer Cell"},{"key":"566_CR131","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1007\/s00441-020-03276-9","volume":"382","author":"A Morita","year":"2020","unstructured":"Morita, A. et al. The process of revascularization in the neonatal mouse retina following short-term blockade of vascular endothelial growth factor receptors. Cell Tissue Res. 382, 529\u2013549 (2020).","journal-title":"Cell Tissue Res."},{"key":"566_CR132","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1083\/jcb.138.3.707","volume":"138","author":"DW Dawson","year":"1997","unstructured":"Dawson, D. W. et al. CD36 mediates the in vitro inhibitory effects of thrombospondin-1 on endothelial cells. J. Cell Biol. 138, 707\u2013717 (1997).","journal-title":"J. Cell Biol."},{"key":"566_CR133","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/nm0603-685","volume":"9","author":"RK Jain","year":"2003","unstructured":"Jain, R. K. Molecular regulation of vessel maturation. Nat. Med. 9, 685\u2013693 (2003).","journal-title":"Nat. Med."},{"key":"566_CR134","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1038\/nature05355","volume":"444","author":"I Noguera-Troise","year":"2006","unstructured":"Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032\u20131037 (2006).","journal-title":"Nature"}],"container-title":["Experimental &amp; Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s12276-021-00566-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s12276-021-00566-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s12276-021-00566-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,29]],"date-time":"2023-01-29T09:03:04Z","timestamp":1674982984000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s12276-021-00566-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2]]},"references-count":134,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,2]]}},"alternative-id":["566"],"URL":"https:\/\/doi.org\/10.1038\/s12276-021-00566-2","relation":{},"ISSN":["1226-3613","2092-6413"],"issn-type":[{"value":"1226-3613","type":"print"},{"value":"2092-6413","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2]]},"assertion":[{"value":"25 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 December 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 February 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}