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Complement-mediated inhibition of neovascularization reveals a point of convergence between innate immunity and angiogenesis
Open accessAbstract
Beyond its role in immunity, complement mediates a wide range of functions in the context of morphogenetic or tissue remodeling processes. Angiogenesis is crucial during tissue remodeling in multiple pathologies; however, the knowledge about the regulation of neovascularization by the complement components is scarce. Here we studied the involvement of complement in pathological angiogenesis. Strikingly, we found that mice deficient in the central complement component C3 displayed increased neovascularization in the model of retinopathy of prematurity (ROP) and in the in vivo Matrigel plug assay. In addition, antibody-mediated blockade of C5, treatment with C5aR antagonist, or C5aR deficiency in mice resulted in enhanced pathological retina angiogenesis. While complement did not directly affect angiogenesis-related endothelial cell functions, we found that macrophages mediated the antiangiogenic activity of complement. In particular, C5a-stimulated macrophages were polarized toward an angiogenesis-inhibitory phenotype, including the up-regulated secretion of the antiangiogenic soluble vascular endothelial growth factor receptor-1. Consistently, macrophage depletion in vivo reversed the increased neovascularization associated with C3- or C5aR deficiency. Taken together, complement and in particular the C5a-C5aR axes are potent inhibitors of angiogenesis.
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“For instance, the anaphylatoxins C3a and C5a have been found to enhance laser-induced CNV in some cases, but may have anti-angiogenic properties in mouse models of retinal hypoxia through the stimulation of mononuclear phagocytes to secrete soluble VEGF receptor 1 that inhibits VEGF [169,170].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [170]
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Pı́o, R., Corrales, L. P., & Lambris, J. D. (2013) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-5915-6_11 · Cited by 199
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C1q as a unique player in angiogenesis with therapeutic implication in wound healing
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“(15) provided compelling evidence that C5a exerts an antiangiogenic effect in a murine model of retinopathy of prematurity, extending previous findings that C5a triggers the release of antiangiogenic factors associated with placental dysfunction and poor pregnancy outcomes (26).”
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The role of the complement system in metabolic organs and metabolic diseases
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“C5aR mice were previously described (22, 23).”
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de Vries, M. R., & Quax, P. H. A. (2016) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000339 · Cited by 110
Complement and macrophage crosstalk during process of angiogenesis in tumor progression
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“C5aR antagonist supported the process of neovascularization, whereas treatment with C5a agonist reduced neovascularization in retinopathy model, confirming the inhibitory role of C5a and C5aR in this process [79].”
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Opposing Roles for Complement Component C5a in Tumor Progression and the Tumor Microenvironment
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“A recent study also demonstrated that C5a negatively regulates neovascularization and angiogenesis via secretion of soluble VEGF receptor 1 (33).”
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“We found that incubation of ovarian cancer cells with a C3amimetic peptide (C3a-receptor agonist peptide) (17) decreased expression of E-cadherin in cancer cells, and incubation with a C3a-receptor antagonist increased E-cadherin (Fig.”
BackgroundA Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy
Hameed, S. S., Vishwakarma, S., Chhablani, J. K., Tyagi, M., Pappuru, R. R., Jakati, S., Chakrabarti, S., & Kaur, I. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00154 · Cited by 95
“Conversely, the anti-angiogenic property of the complement system in a ROP mouse model was also documented, where it was shown that C3 and C5aR were required for inhibiting the polarization of macrophage toward its angiogenic potential (10).”
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“They have been shown to influence processes as diverse as angiogenesis (45) or asthma (46), histamine release or vasoconstriction (47), and generally mediate leukocyte activation and recruitment (48).”
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Kim, B. J., Mastellos, D. C., Li, Y., Dunaief, J. L., & Lambris, J. D. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100936 · Cited by 92
Self-citationComplement anaphylatoxin C3a is a potent inducer of embryonic chick retina regeneration
Haynes, T., Luz-Madrigal, A., Reis, E. S., Echeverri Ruiz, N. P., Grajales-Esquivel, E., Tzekou, A., Tsonis, P. A., Lambris, J. D., & Del Rio-Tsonis, K. (2013) · Nature Communications · doi:10.1038/ncomms3312 · Cited by 87
Self-citationThe role of the immune system in central nervous system plasticity after acute injury
Peruzzotti‐Jametti, L., Donegà, M., Giusto, E., Mallucci, G., Marchetti, B., & Pluchino, S. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.04.036 · Cited by 86
“…2008; Ishii et al., 2012) NAA (modulation of H2O2-induced apoptosis) (Warrington et al., 2004; Mantovani et al., 2011) Angiogenesis C5 (Norrby, 2002; Langer et al., 2010) VEGF (Scapini et al., 2004; Ribatti et al., 2011), MMP-9 (Justicia et al., 2003; Riboldi et al., 2005) PDGF, TNF-α and VEGF…”
A Novel Function of Junctional Adhesion Molecule-C in Mediating Melanoma Cell Metastasis
Langer, H. F., Orlova, V. V., Xie, C., Kaul, S. C., Schneider, D., Lonsdorf, A. S., Sauter, M., Choi, E. Y., Dutoit, V., Pellegrini, M., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-2794 · Cited by 84
“Proliferation assay B16 cell proliferation was carried out as described (25, 26).”
Self-citationPlatelets induce apoptosis via membrane-bound FasL
Schleicher, R., Reichenbach, F., Kraft, P., Kumar, A., Lescan, M., Todt, F., Göbel, K., Hilgendorf, I., Geisler, T., Bauer, A., et al. (2015) · Blood · doi:10.1182/blood-2013-12-544445 · Cited by 85
“Bonemarrow-derivedmacrophageswere isolated as described previously.(37) The medium was changed every second day, loosely adherent dendritic cells were removed after 1 week, and the adherent macrophages were collected and used for experiments.”
MethodSelf-citationComplement deficiency promotes cutaneous wound healing in mice
Rafail, S., Kourtzelis, I., Foukas, P. G., Markiewski, M. M., DeAngelis, R. A., Guariento, M., Ricklin, D., Grice, E. A., & Lambris, J. D. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1402354 · Cited by 72
“Apart from the role of complement on immune cells, recent work has also shown the involvement of complement in other key processes playing roles in wound healing, such as fibroblast migration and activation (40), angiogenesis (9, 21), and coagulation (41).”
BackgroundMethodResultSelf-citationComplement links platelets to innate immunity
Nording, H., & Langer, H. F. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2018.01.003 · Cited by 75
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Abnormal Complement Activation and Inflammation in the Pathogenesis of Retinopathy of Prematurity
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“As was demonstrated in an OIR mouse model, complement factors C3a and C5a activate macrophages by binding to C3aR and C5aR, thereby regulating angiogenesis (38).”
BackgroundImplications of genetic variation in the complement system in age-related macular degeneration
de Jong, S., Gagliardi, G., Garanto, A., de Breuk, A., Lechanteur, Y. T. E., Katti, S., van den Heuvel, L. P., Volokhina, E. B., & den Hollander, A. I. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2021.100952 · Cited by 71
Targeting complement-mediated immunoregulation for cancer immunotherapy
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Complement activation in animal and human pregnancies as a model for immunological recognition
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“This is in contrast to results in other angiogenesis assays where complement inhibition was found to increase neovascularization in hypoxiainduced retinal neovascularization and in VEGF-triggered Matrigel angiogenesis assays (Langer et al., 2010).”
ResultA Novel Role of Complement in Retinal Degeneration
Yu, M., Zou, W., Peachey, N. S., McIntyre, T. M., & Liu, J. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.12-10069 · Cited by 63
“At older ages, we noted ONL thinning and disorganization in mice lacking C3aR (either C3aR / or C3aR / C5aR / ) but not C5aR.”
BackgroundInfluentialThe Complement System Is Critical in Maintaining Retinal Integrity during Aging
Mukai, R., Okunuki, Y., Husain, D., Kim, C. B., Lambris, J. D., & Connor, K. M. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00015 · Cited by 61
“…processes, including photoreceptor degeneration, vascular regression, ischemia/reperfusion injury, sepsis, stroke, autoimmunity, and inflammatory disorders (Guo et al., 2005; Walsh et al., 2005; Sjoberg et al., 2009; Langer et al., 2010; Ricklin et al., 2010; Sweigard et al., 2014, 2015).”
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“Effect of PMX205 on NT and arginase I expression C5a stimulation of murine macrophages polarizes the cells towards the M1 phenotype with increased IL-6, TNF and low IL-10 (Langer et al., 2010).”
BackgroundInfluentialComplement activation in the context of stem cells and tissue repair
Schraufstätter, I. U. (2015) · World Journal of Stem Cells · doi:10.4252/wjsc.v7.i8.1090 · Cited by 60
Wang, C., Lee, Y., Chang, C., Lin, Y., Liou, Y.-A., Hsu, P.-C., Chang, C.-C., Sai, A., Wang, C., & Chao, T. (2022) · Cancers · doi:10.3390/cancers14071651 · Cited by 59
“The antiangiogenic factor was upregulated in monocytes by complement activation [23].”
BackgroundObesity “complements” preeclampsia
Olson, K. N., Redman, L. M., & Sones, J. L. (2019) · Physiological Genomics · doi:10.1152/physiolgenomics.00102.2018 · Cited by 61
“Moreover, C5a increased the expression of antiangiogenic factors including TNF- and sFlt-1 and, in tandem, decreased expression of Physiol Genomics • doi:10.1152/physiolgenomics.00102.2018 • www.physiolgenomics.org proangiogenic PlGF and anti-inflammatory IL-10 in trophoblast cells, all of which have been implicated a…”
BackgroundInfluentialThe Complement System in Inflammatory Bowel Disease
Jain, U., Otley, A. R., Limbergen, J. V., & Stadnyk, A. W. (2014) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000000056 · Cited by 56
“In this regard, C5a stimulates dendritic cells to promote the development of selected Th cells,(93) and the M1 (inflammatory) macrophage phenotype.(94) C5a can also directly provide survival signals to T cells by inhibiting apoptosis.”
BackgroundComplement factor C5a as mast cell activator mediates vascular remodelling in vein graft disease
de Vries, M. R., Wezel, A., Schepers, A., van Santbrink, P. J., Woodruff, T. M., Niessen, H. W. M., Hamming, J. F., Kuiper, J., Bot, I., & Quax, P. H. A. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs312 · Cited by 55
Terminal Complement Activation in Preeclampsia
Burwick, R. M., Velásquez-Penagos, J. A., Valencia, C. M. M., Gutiérrez-Marín, J. H., Edna-Estrada, F., Silva, J. L., Trujillo-Otálvaro, J., Vargas-Rodríguez, J., Bernal, Y., Quintero, A., et al. (2018) · Obstetrics and Gynecology · doi:10.1097/aog.0000000000002980 · Cited by 55
Complement regulation in the eye: implications for age-related macular degeneration
Wilke, G. A., & Apte, R. S. (2024) · Journal of Clinical Investigation · doi:10.1172/jci178296 · Cited by 55
“Interestingly, C3-deficient mice developed increased neovascularization in a model of retinopathy of prematurity; the same study found that macrophages stimulated with C5a displayed an antiangiogenesis phenotype, suggesting complement could play a role in regulating angiogenesis in the retina (129).”
Anaphylatoxins coordinate innate and adaptive immune responses in allergic asthma
Schmudde, I., Laumonnier, Y., & Köhl, J. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.04.009 · Cited by 54
The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets
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“Whole-mount tracheas were evaluated for microvascular perfusion by fluorescence staining techniques as described previously by (3, 38).”
The dual role of complement in cancer and its implication in anti-tumor therapy
Kourtzelis, I., & Rafail, S. (2016) · Annals of Translational Medicine · doi:10.21037/atm.2016.06.26 · Cited by 55
“showed, both in vitro and in a model of retinopathy of prematurity, that the deficiency in C3 or C5aR resulted in more neovascularization and angiogenesis (71).”
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Complement 5a‐mediated trophoblasts dysfunction is involved in the development of pre‐eclampsia
Ma, Y., Kong, L., Ge, Q., Lu, Y., Hong, M., Zhang, Y., Ruan, C., & Gao, P. (2017) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13466 · Cited by 52
“C5a is also reported to be an angiogenic factor, which exerts a crucial role in stimulating macrophages towards an angiogenesis-inhibitory phenotype in the model of retinopathy of prematurity [32].”
BackgroundBandini, S., Curcio, C., Macagno, M., Quaglino, E., Arigoni, M., Lanzardo, S., Hysi, A., Barutello, G., Consolino, L., Longo, D. L., et al. (2013) · OncoImmunology · doi:10.4161/onci.26137 · Cited by 50
“Nevertheless, beyond its role in immunity, the complement system is also involved in tissue remodeling processes, including neo-angiogenesis.(30) Whether the complement exerts pro- or anti-angiogenic functions is still controversial.”
Recknagel, S., Bindl, R., Kurz, J., Wehner, T., Schoengraf, P., Ehrnthaller, C., Qu, H., Gebhard, F. T., Huber-Lang, M. S., Lambris, J. D., et al. (2011) · Journal of Orthopaedic Research® · doi:10.1002/jor.21561 · Cited by 49
“Control animals received a peptide (Ac-F[OPdChaAdR]) with two changed amino acids, which does not have antagonistic activity and thus does not develop any biological effect at the same concentration and at the same time points.(22)”
BackgroundSelf-citationExpression of anaphylatoxin receptors on platelets in patients with coronary heart disease
Patzelt, J., Mueller, K. A. L., Breuning, S., Karathanos, A., Schleicher, R., Seizer, P., Gawaz, M., Langer, H. F., & Geisler, T. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.12.002 · Cited by 48
Self-citationInhibition of the alternative complement pathway preserves photoreceptors after retinal injury
Sweigard, J. H., Matsumoto, H., Smith, K. E., Kim, L. A., Paschalis, E. I., Okonuki, Y., Castillejos, A. G., Kataoka, K., Hasegawa, E., Yanai, R., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aab1482 · Cited by 48
Self-citationKim, H., Erdman, L. K., Lu, Z., Serghides, L., Zhong, K., Dhabangi, A., Musoke, C., Gerard, C. J., Cserti-Gazdewich, C. M., Liles, W. C., et al. (2013) · Infection and Immunity · doi:10.1128/iai.01246-13 · Cited by 48
Kadoch, C., Li, J., Wong, V. S., Chen, L., Cha, S., Münster, P. N., Lowell, C. A., Shuman, M. A., & Rubenstein, J. L. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0474 · Cited by 48
“C3 and C3a may also regulate lymphoma-associated vascular permeability and/or angiogenesis, a possibility supported by recent observations about the antiangiogenic effects of C3a and C5a on retinal vasculature (53).”
BackgroundAngiogenic and Antiangiogenic Chemokines
Bosisio, D., Salvi, V., Gagliostro, V., & Sozzani, S. (2013) · Chemical immunology/Fortschritte der Allergielehre/Progress in allergy/Chemical immunology and allergy · doi:10.1159/000353317 · Cited by 46
The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis
Bandini, S., Macagno, M., Hysi, A., Lanzardo, S., Conti, L., Bello, A., Riccardo, F., Ruiu, R., Merighi, I. F., Forni, G., et al. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1253653 · Cited by 46
“Contradictory effects of complement in modulating vascularization and angiogenesis are described in the literature.(30,31,43)”
BackgroundHammadi, S., Tzoumas, N., Ferrara, M., Meschede, I. P., Lo, K., Harris, C., Lako, M., & Steel, D. H. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082870 · Cited by 44
“This method has been particularly successful in the treatment of vascular retinal disorders such as neovascular AMD through the use of anti-VEGF agents.”
BackgroundInfluentialWeiß, S., Rosendahl, A., Czesla, D., Meyer‐Schwesinger, C., Stahl, R. A. K., Ehmke, H., Kurts, C., Zipfel, P. F., Köhl, J., & Wenzel, U. O. (2016) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00040.2016 · Cited by 46
Elevated Soluble Flt1 Inhibits Endothelial Repair in PR3-ANCA–Associated Vasculitis
Roux, S. L., Pepper, R. J., Dufay, A., Néel, M., Meffray, E., Lamandé, N., Rimbert, M., Josien, R., Hamidou, M. A., Hourmant, M., et al. (2011) · Journal of the American Society of Nephrology · doi:10.1681/asn.2010080858 · Cited by 44
Jain, R., Poisson, L., Narang, J., Scarpace, L. M., Rosenblum, M. L., Rempel, S. A., & Mikkelsen, T. (2012) · American Journal of Neuroradiology · doi:10.3174/ajnr.a2956 · Cited by 43
“…intheregulationoftheangiogenesispathway(GO:0045766, GO:0016525),ofwhich19genes(31probes)hadsignificant correlationwithPS(Fig2andOn-lineTable5 4,16-34 ), whereas 9 genes (26 probes) had significant correlation with CBV ( P (cid:1) .05) (Fig 2 and On-line Table 6 21,22,24,27,31,35-39 ).”
McDonald, C. R., Cahill, L. S., Ho, K. T., Yang, J., Kim, H., Silver, K., Ward, P. A., Mount, H. T. J., Liles, W. C., Sled, J. G., et al. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1005140 · Cited by 42
“Overall this finding is consistent with previous observations that malaria also alters placental vascular development [5,10,60,61].”
Du, Y., Teng, X., Wang, N., Zhang, X., Chen, J., Ding, P., Qiao, Q., Wang, Q., Zhang, L., Yang, C., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.525501 · Cited by 41
“Antip65 (17-10060), anti-c-Rel (09-040), anti-RelB (EP613Y), antiCREB (AB3006), and anti-phospho-CREB (Ser-133) (17-1013) antibodies, all used only for chromatin immunoprecipitation (ChIP) assays, and the anti-acetyl-TP53 (Lys-373) (06-916) antibody were obtained from Millipore (Billerica, MA).”
BackgroundMethodC5L2 receptor disruption enhances the development of diet-induced insulin resistance in mice
Fisette, A., Munkonda, M. N., Οικονομοπούλου, Κ., Paglialunga, S., Lambris, J. D., & Cianflone, K. (2012) · Immunobiology · doi:10.1016/j.imbio.2012.04.001 · Cited by 41
Self-citationCharacterization of the LPS-induced inflammation of the adrenal gland in mice
Kanczkowski, W., Chatzigeorgiou, A., Samus, M., Tran, N., Zacharowski, K. D., Chavakis, T., & Bornstein, S. R. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.12.020 · Cited by 40
Self-citationThe Role of Chemoattractant Receptors in Shaping the Tumor Microenvironment
Zhou, J., Xiang, Y., Yoshimura, T., Chen, K., Gong, W., Huang, J., Zhou, Y., Yao, X., Bian, X., & Wang, J. (2014) · BioMed Research International · doi:10.1155/2014/751392 · Cited by 44
Urinary Excretion of C5b‐9 is Associated With the Anti‐Angiogenic State in Severe Preeclampsia
Guseh, S. H., Feinberg, B. B., Dawood, H. Y., Yamamoto, H. S., Fichorova, R. N., & Burwick, R. M. (2014) · American Journal of Reproductive Immunology · doi:10.1111/aji.12349 · Cited by 40
The alternative complement pathway regulates pathological angiogenesis in the retina
Sweigard, J. H., Yanai, R., Gaissert, P., Saint‐Geniez, M., Kataoka, K., Thanos, A., Stahl, G. L., Lambris, J. D., & Connor, K. M. (2014) · The FASEB Journal · doi:10.1096/fj.14-251041 · Cited by 38
“By combining the results of the previous study (12) with those of our work, we can begin to formulate a mechanism for how the alternative pathway orchestrates the removal of neovessels.”
BackgroundResultSelf-citationPark, Y. J., Woo, S. J., Kim, Y. M., Hong, S., Lee, Y. E., & Park, K. H. (2019) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.19-27258 · Cited by 39
“In support of our view, Langer et al.(28)”
ResultWells, L. A., Guo, H., Emili, A., & Sefton, M. V. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2016.11.036 · Cited by 40
Jensen, E. G., Jakobsen, T. S., Thiel, S., Askou, A. L., & Corydon, T. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249752 · Cited by 40
“More research is, however, needed concerning anaphylatoxins in the different stages of CNV [3] and the roles of macrophages as their facilitators [173].”
BackgroundAssessment of blood-brain barrier integrity and neuroinflammation in preeclampsia
Burwick, R. M., Togioka, B. M., Speranza, R. J., Gaffney, J. E., Roberts, V. H. J., Frias, A. E., & Rincon, M. P. (2019) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2019.06.024 · Cited by 35
Complement C3a promotes proliferation, migration and stemness in cutaneous squamous cell carcinoma
Zhuo, F., Qin, J., Wang, D., & Geng, S. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13959 · Cited by 36
“A431 and SCC13 cells were exposed to a human C3a peptide agonist, as described in a previous study.(22) A431 and SCC13 cells were treated with 0.”
MethodThe Role of Complement in Angiogenesis
Markiewski, M. M., Daugherity, E. A., Reese, B., & Karbowniczek, M. (2020) · Antibodies · doi:10.3390/antib9040067 · Cited by 40
“In addition, C5 neutralization by monoclonal antibody, C5aR1 blockade by PMX53, and C5aR1 deficiency led to increased vascularization of retina in ROP [59].”
BackgroundResultInfluentialAmeln, A. K., Cremer, S., Hoffmann, J., Schuster, P., Khedr, S., Korovina, I., Troullinaki, M., Neuwirth, A., Sprott, D., Chatzigeorgiou, A., et al. (2017) · Thrombosis and Haemostasis · doi:10.1160/th16-05-0354 · Cited by 34
Self-citationYednock, T. A., Fong, D. S., & Lad, E. M. (2022) · International Journal of Retina and Vitreous · doi:10.1186/s40942-022-00431-y · Cited by 35
“A potential explanation may be that, although C3 and C5 inhibition prevent neovascularization in several acute models used for GA, it can promote neovascularization in other models of retinal damage [79] or can prevent tissue repair [80–84].”
BackgroundComplement Involvement in Neovascular Ocular Diseases
Yanai, R., Thanos, A., & Connor, K. M. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-0106-3_10 · Cited by 35
Kourtzelis, I., Magnusson, P., Kotlabová, K., Lambris, J. D., & Chavakis, T. (2015) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-18603-0_11 · Cited by 28
Self-citationRole of NOD- like Receptors in Glioma Angiogenesis: Insights into future therapeutic interventions
Saxena, S., & Jha, S. (2017) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2017.02.001 · Cited by 34
“Several research findings support a link between innate immunity and angiogenesis [14,20,21].”
BackgroundJanneh, A. H., Kassir, M. F., Atilgan, F. C., Lee, H. G., Sheridan, M., Oleinik, N. V., Szulc, Z. M., Voelkel‐Johnson, C., Nguyen, H. D., Li, H., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111742 · Cited by 32
Zhao, P., Wu, J., Lu, F., Peng, X., Liu, C., Zhou, N., & Ying, M. (2019) · BMC Cancer · doi:10.1186/s12885-019-5422-x · Cited by 32
“C3a and C5a are inhibitory effectors of pathological hypoxia-driven retinal neovascularization in the C3−/− or C5aR−/− mouse retinopathy model [21].”
BackgroundThiol pathways in the regulation of tissue factor prothrombotic activity
Versteeg, H. H., & Ruf, W. (2011) · Current Opinion in Hematology · doi:10.1097/moh.0b013e32834981de · Cited by 32
Budkowska, M., Ostrycharz, E., Wojtowicz, A., Marcinowska, Z., Woźniak, J., Ratajczak, M. Z., & Dołęgowska, B. (2018) · Stem Cell Reviews and Reports · doi:10.1007/s12015-018-9836-7 · Cited by 31
“In addition to regulating the mobilization of HSPCs [34], it affects the coagulation system [35], angiogenesis [36], tissue regeneration [37] and lipid metabolism [38].”
BackgroundJia, C., Zhu, W., Ren, S., Xi, H., Li, S., & Wang, Y. (2011) · Europe PMC (PubMed Central) · Cited by 28
Sun, M. M., Wadehra, M., Casero, D., Lin, M., Aguirre, B., Parikh, S., Matynia, A., Gordon, L. K., & Chu, A. (2020) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.61.2.3 · Cited by 27
Complement involvement in kidney diseases: From physiopathology to therapeutical targeting
Salvadori, M. (2015) · World Journal of Nephrology · doi:10.5527/wjn.v4.i2.169 · Cited by 26
The role of complement in the tumor microenvironment
Ain, D., Shaikh, T., Manimala, S., & Ghebrehiwet, B. (2021) · Faculty Reviews · doi:10.12703/r/10-80 · Cited by 26
McDonald, C. R., Elphinstone, R. E., & Kain, K. C. (2013) · Trends in Parasitology · doi:10.1016/j.pt.2013.03.005 · Cited by 27
Complement Activation in Placental Malaria
McDonald, C. R., Tran, V., & Kain, K. C. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.01460 · Cited by 26
Metadata
- Authors
- Langer, H. F., Chung, K.-J., Orlova, V. V., Choi, E. Y., Kaul, S., Kruhlak, M. J., Alatsatianos, M., DeAngelis, R. A., Roche, P. A., Magotti, P., Li, X., Economopoulou, M., Rafail, S., Lambris, J. D., & Chavakis, T.
- Affiliations
- National Institutes of Health (US)
- University of Pennsylvania (US)
- Corresponding author
- Lambris, John D.
- Chavakis, Triantafyllos
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-11-25
- Volume
- 116
- Issue
- 22
- Pages
- 4395-4403
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2996109
- OpenAlex
- W2165915271
- Cited by
- 176
- References
- 58
- Citations by year
- 2025: 8 · 2024: 8 · 2023: 9 · 2022: 9 · 2021: 8 · 2020: 9 · 2019: 13 · 2018: 15 · 2017: 8 · 2016: 13 · 2015: 16 · 2014: 12 · 2013: 16 · 2012: 14
- FWCI
- 6.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA112162, CA-112162)
- National Institute of Allergy and Infectious Diseases (AI 068730, P01AI068730)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- complement system, neovascularization, pathological angiogenesis, complement C3, C5a, C5a receptor, retinopathy of prematurity, macrophages, macrophage polarization, soluble VEGFR1, antiangiogenic activity, innate immunity, tissue remodeling
- MeSH terms
- Animals, Cell Line, Complement C3, Complement C5, Humans, Immunity, Innate, Infant, Newborn, Macrophages, Mice, Inbred C57BL, Neovascularization, Pathologic, Retina, Retinopathy of Prematurity, Complement C5a, Gene Deletion, Cell Culture Techniques, Vascular Endothelial Growth Factors, Receptor, Anaphylatoxin C5a, Mice
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