CD146 as a promising therapeutic target for retinal and choroidal neovascularization diseases.
CD146
VEGF
angiogenesis
combined treatment
ocular diseases
Journal
Science China. Life sciences
ISSN: 1869-1889
Titre abrégé: Sci China Life Sci
Pays: China
ID NLM: 101529880
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
13
08
2021
accepted:
20
10
2021
pubmed:
4
11
2021
medline:
10
6
2022
entrez:
3
11
2021
Statut:
ppublish
Résumé
Blood vessel dysfunction causes several retinal diseases, including diabetic retinopathy, familial exudative vitreoretinopathy, macular degeneration and choroidal neovascularization in pathological myopia. Vascular endothelial growth factor (VEGF)-neutralizing proteins provide benefits in most of those diseases, yet unsolved haemorrhage and frequent intraocular injections still bothered patients. Here, we identified endothelial CD146 as a new target for retinal diseases. CD146 expression was activated in two ocular pathological angiogenesis models, a laser-induced choroid neovascularization model and an oxygen-induced retinopathy model. The absence of CD146 impaired hypoxia-induced cell migration and angiogenesis both in cell lines and animal model. Preventive or therapeutic treatment with anti-CD146 antibody AA98 significantly inhibited hypoxia-induced aberrant retinal angiogenesis in two retinal disease models. Mechanistically, under hypoxia condition, CD146 was involved in the activation of NFκB, Erk and Akt signalling pathways, which are partially independent of VEGF. Consistently, anti-CD146 therapy combined with anti-VEGF therapy showed enhanced impairment effect of hypoxia-induced angiogenesis in vitro and in vivo. Given the critical role of abnormal angiogenesis in retinal and choroidal diseases, our results provide novel insights into combinatorial therapy for neovascular fundus diseases.
Identifiants
pubmed: 34729700
doi: 10.1007/s11427-021-2020-0
pii: 10.1007/s11427-021-2020-0
doi:
Substances chimiques
CD146 Antigen
0
Vascular Endothelial Growth Factor A
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1157-1170Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Bautch, V.L. (2012). VEGF-directed blood vessel patterning: from cells to organism. Cold Spring Harb Perspect Med 2, a006452.
pubmed: 22951440
pmcid: 3426816
doi: 10.1101/cshperspect.a006452
Bu, P., Gao, L., Zhuang, J., Feng, J., Yang, D., and Yan, X. (2006). Anti-CD146 monoclonal antibody AA98 inhibits angiogenesis via suppression of nuclear factor-κB activation. Mol Cancer Ther 5, 2872–2878.
pubmed: 17121934
doi: 10.1158/1535-7163.MCT-06-0260
Cascone, T., Herynk, M.H., Xu, L., Du, Z., Kadara, H., Nilsson, M.B., Oborn, C.J., Park, Y.Y., Erez, B., Jacoby, J.J., et al. (2011). Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma. J Clin Invest 121, 1313–1328.
pubmed: 21436589
pmcid: 3070607
doi: 10.1172/JCI42405
Chan-Ling, T., Gole, G.A., Quinn, G.E., Adamson, S.J., and Darlow, B.A. (2018). Pathophysiology, screening and treatment of ROP: a multi-disciplinary perspective. Prog Retinal Eye Res 62, 77–119.
doi: 10.1016/j.preteyeres.2017.09.002
Chen, J., Luo, Y., Hui, H., Cai, T., Huang, H., Yang, F., Feng, J., Zhang, J., and Yan, X. (2017). CD146 coordinates brain endothelial cell-pericyte communication for blood-brain barrier development. Proc Natl Acad Sci USA 114, E7622–E7631.
pubmed: 28827364
pmcid: 5594696
doi: 10.1073/pnas.1710848114
Chen, X., Yan, H., Liu, D., Xu, Q., Duan, H., Feng, J., Yan, X., and Xie, C. (2021). Structure basis for AA98 inhibition on the activation of endothelial cells mediated by CD146. iScience 24, 102417.
pubmed: 33997697
pmcid: 8093899
doi: 10.1016/j.isci.2021.102417
Colomb, F., Wang, W., Simpson, D., Zafar, M., Beynon, R., Rhodes, J.M., and Yu, L.G. (2017). Galectin-3 interacts with the cell-surface glycoprotein CD146 (MCAM, MUC18) and induces secretion of metastasis-promoting cytokines from vascular endothelial cells. J Biol Chem 292, 8381–8389.
pubmed: 28364041
pmcid: 5437243
doi: 10.1074/jbc.M117.783431
Connor, K.M., Krah, N.M., Dennison, R.J., Aderman, C.M., Chen, J., Guerin, K.I., Sapieha, P., Stahl, A., Willett, K.L., and Smith, L.E.H. (2009). Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc 4, 1565–1573.
pubmed: 19816419
pmcid: 3731997
doi: 10.1038/nprot.2009.187
Duan, H., Xing, S., Luo, Y., Feng, L., Gramaglia, I., Zhang, Y., Lu, D., Zeng, Q., Fan, K., Feng, J., et al. (2013). Targeting endothelial CD146 attenuates neuroinflammation by limiting lymphocyte extravasation to the CNS. Sci Rep 3, 1687.
pubmed: 23595028
pmcid: 3629416
doi: 10.1038/srep01687
Duan, H., Zhao, S., Xiang, J., Ju, C., Chen, X., Gramaglia, I., and Yan, X. (2021). Targeting the CD146/Galectin-9 axis protects the integrity of the blood-brain barrier in experimental cerebral malaria. Cell Mol Immunol 18, 2443–2454.
pubmed: 33203936
doi: 10.1038/s41423-020-00582-8
Flanagan, K., Fitzgerald, K., Baker, J., Regnstrom, K., Gardai, S., Bard, F., Mocci, S., Seto, P., You, M., Larochelle, C., et al. (2012). Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS. PLoS ONE 7, e40443.
pubmed: 22792325
pmcid: 3391262
doi: 10.1371/journal.pone.0040443
Flaxman, S.R., Bourne, R.R.A., Resnikoff, S., Ackland, P., Braithwaite, T., Cicinelli, M.V., Das, A., Jonas, J.B., Keeffe, J., Kempen, J.H., et al. (2017). Global causes of blindness and distance vision impairment 1990–2020: a systematic review and meta-analysis. Lancet Glob Health 5, e1221–e1234.
pubmed: 29032195
doi: 10.1016/S2214-109X(17)30393-5
Halt, K.J., Pärssinen, H.E., Junttila, S.M., Saarela, U., Sims-Lucas, S., Koivunen, P., Myllyharju, J., Quaggin, S., Skovorodkin, I.N., and Vainio, S.J. (2016). CD146
pubmed: 27165833
doi: 10.1016/j.kint.2016.02.021
Higuchi, T., Fujiwara, H., Egawa, H., Sato, Y., Yoshioka, S., Tatsumi, K., Itoh, K., Maeda, M., Fujita, J., and Fujii, S. (2003). Cyclic AMP enhances the expression of an extravillous trophoblast marker, melanoma cell adhesion molecule, in choriocarcinoma cell JEG3 and human chorionic villous explant cultures. Mol Hum Reprod 9, 359–366.
pubmed: 12771237
doi: 10.1093/molehr/gag044
Hiroi, S., Taira, E., Ogawa, K., and Tsukamoto, Y. (2005). Neurite extension of DRG neurons by gicerin expression is enhanced by nerve growth factor. Int J Mol Med 16, 1009–1014.
pubmed: 16273279
Holz, F.G., Schmitz-Valckenberg, S., and Fleckenstein, M. (2014). Recent developments in the treatment of age-related macular degeneration. J Clin Invest 124, 1430–1438.
pubmed: 24691477
pmcid: 3973093
doi: 10.1172/JCI71029
Ishikawa, T., Wondimu, Z., Oikawa, Y., Gentilcore, G., Kiessling, R., Egyhazi Brage, S., Hansson, J., and Patarroyo, M. (2014). Laminins 411 and 421 differentially promote tumor cell migration via α6β1 integrin and MCAM (CD146). Matrix Biol 38, 69–83.
pubmed: 24951930
doi: 10.1016/j.matbio.2014.06.002
Jiang, T., Zhuang, J., Duan, H., Luo, Y., Zeng, Q., Fan, K., Yan, H., Lu, D., Ye, Z., Hao, J., et al. (2012). CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. Blood 120, 2330–2339.
pubmed: 22718841
doi: 10.1182/blood-2012-01-406108
Jouve, N., Despoix, N., Espeli, M., Gauthier, L., Cypowyj, S., Fallague, K., Schiff, C., Dignat-George, F., Vély, F., and Leroyer, A.S. (2013). The involvement of CD146 and its novel ligand Galectin-1 in apoptotic regulation of endothelial cells. J Biol Chem 288, 2571–2579.
pubmed: 23223580
doi: 10.1074/jbc.M112.418848
Kang, Y., Wang, F., Feng, J., Yang, D., Yang, X., and Yan, X. (2006). Knockdown of CD146 reduces the migration and proliferation of human endothelial cells. Cell Res 16, 313–318.
pubmed: 16541130
doi: 10.1038/sj.cr.7310039
Kim, S.H., Kim, H., Ku, H.J., Park, J.H., Cha, H., Lee, S., Lee, J.H., and Park, J.W. (2016). Oxalomalate reduces expression and secretion of vascular endothelial growth factor in the retinal pigment epithelium and inhibits angiogenesis: implications for age-related macular degeneration. Redox Biol 10, 211–220.
pubmed: 27810736
pmcid: 5094379
doi: 10.1016/j.redox.2016.10.008
Lambert, V., Lecomte, J., Hansen, S., Blacher, S., Gonzalez, M.L.A., Struman, I., Sounni, N.E., Rozet, E., de Tullio, P., Foidart, J.M., et al. (2013). Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice. Nat Protoc 8, 2197–2211.
pubmed: 24136346
doi: 10.1038/nprot.2013.135
Luo, Y., Duan, H., Qian, Y., Feng, L., Wu, Z., Wang, F., Feng, J., Yang, D., Qin, Z., and Yan, X. (2017). Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis. Cell Res 27, 352–372.
pubmed: 28084332
pmcid: 5339843
doi: 10.1038/cr.2017.8
Luo, Y., Teng, X., Zhang, L., Chen, J., Liu, Z., Chen, X., Zhao, S., Yang, S., Feng, J., and Yan, X. (2019). CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension. Nat Commun 10, 3551.
pubmed: 31391533
pmcid: 6686016
doi: 10.1038/s41467-019-11500-6
Mangahas, C.R., dela Cruz, G.V., Schneider, R.J., and Jamal, S. (2004). Endothelin-1 upregulates MCAM in melanocytes. J Invest Dermatol 123, 1135–1139.
pubmed: 15610525
doi: 10.1111/j.0022-202X.2004.23480.x
Mettu, P.S., Allingham, M.J., and Cousins, S.W. (2021). Incomplete response to Anti-VEGF therapy in neovascular AMD: Exploring disease mechanisms and therapeutic opportunities. Prog Retinal Eye Res 82, 100906.
doi: 10.1016/j.preteyeres.2020.100906
Neidhart, M., Wehrli, R., Bruhlmann, P., Michel, B.A., Gay, R.E., and Gay, S. (1999). Synovial fluid CD146 (MUC18), a marker for synovial membrane angiogenesis in rheumatoid arthritis. Arthritis Rheumatism 42, 622–630.
pubmed: 10211875
doi: 10.1002/1529-0131(199904)42:4<622::AID-ANR4>3.0.CO;2-Y
Prager, G.W., Poettler, M., Unseld, M., and Zielinski, C.C. (2012). Angiogenesis in cancer: Anti-VEGF escape mechanisms. Transl Lung Cancer Res 1, 14–25.
pubmed: 25806151
pmcid: 4367591
Rivera, J.C., Holm, M., Austeng, D., Morken, T.S., Zhou, T.E., Beaudry-Richard, A., Sierra, E.M., Dammann, O., and Chemtob, S. (2017). Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies. J Neuroinflamm 14, 165.
doi: 10.1186/s12974-017-0943-1
Ruma, I.M.W., Putranto, E.W., Kondo, E., Murata, H., Watanabe, M., Huang, P., Kinoshita, R., Futami, J., Inoue, Y., Yamauchi, A., et al. (2016). MCAM, as a novel receptor for S100A8/A9, mediates progression of malignant melanoma through prominent activation of NF-κB and ROS formation upon ligand binding. Clin Exp Metastasis 33, 609–627.
pubmed: 27151304
doi: 10.1007/s10585-016-9801-2
Schön, M., Kähne, T., Gollnick, H., and Schön, M.P. (2005). Expression of gp130 in tumors and inflammatory disorders of the skin: formal proof of its identity as CD146 (MUC18, Mel-CAM). J Invest Dermatol 125, 353–363.
pubmed: 16098047
doi: 10.1111/j.0022-202X.2005.23808.x
Scortegagna, M., Cataisson, C., Martin, R.J., Hicklin, D.J., Schreiber, R.D., Yuspa, S.H., and Arbeit, J.M. (2008). HIF-1α regulates epithelial inflammation by cell autonomous NFκB activation and paracrine stromal remodeling. Blood 111, 3343–3354.
pubmed: 18199827
pmcid: 2275004
doi: 10.1182/blood-2007-10-115758
Shao, R., Hamel, K., Petersen, L., Cao, Q.J., Arenas, R.B., Bigelow, C., Bentley, B., and Yan, W. (2009). YKL-40, a secreted glycoprotein, promotes tumor angiogenesis. Oncogene 28, 4456–4468.
pubmed: 19767768
pmcid: 2795793
doi: 10.1038/onc.2009.292
Simon, G.C., Martin, R.J., Smith, S., Thaikoottathil, J., Bowler, R.P., Barenkamp, S.J., and Chu, H.W. (2011). Up-regulation of MUC18 in airway epithelial cells by IL-13. Am J Respir Cell Mol Biol 44, 606–613.
pubmed: 21239604
pmcid: 3095981
doi: 10.1165/rcmb.2010-0384OC
St Croix, B. (2015). CD146: the unveiling of a pro-angiogenic netrin receptor. Cell Res 25, 533–534.
pubmed: 25849249
pmcid: 4423082
doi: 10.1038/cr.2015.42
Tsuchiya, S., Tsukamoto, Y., Taira, E., and LaMarre, J. (2007). Involvement of transforming growth factor-beta in the expression of gicerin, a cell adhesion molecule, in the regeneration of hepatocytes. Int J Mol Med 19, 381–386.
pubmed: 17273784
Tu, T., Zhang, C., Yan, H., Luo, Y., Kong, R., Wen, P., Ye, Z., Chen, J., Feng, J., Liu, F., et al. (2015). CD146 acts as a novel receptor for netrin-1 in promoting angiogenesis and vascular development. Cell Res 25, 275–287.
pubmed: 25656845
pmcid: 4349246
doi: 10.1038/cr.2015.15
Tugues, S., Koch, S., Gualandi, L., Li, X., and Claesson-Welsh, L. (2011). Vascular endothelial growth factors and receptors: anti-angiogenic therapy in the treatment of cancer. Mol Aspects Med 32, 88–111.
pubmed: 21565214
doi: 10.1016/j.mam.2011.04.004
Vujosevic, S., Aldington, S.J., Silva, P., Hernández, C., Scanlon, P., Peto, T., and Simó, R. (2020). Screening for diabetic retinopathy: new perspectives and challenges. Lancet Diabetes Endocrinol 8, 337–347.
pubmed: 32113513
doi: 10.1016/S2213-8587(19)30411-5
Wang, N., Fan, Y., Ni, P., Wang, F., Gao, X., Xue, Q., and Tang, L. (2008). High glucose effect on the role of CD146 in human proximal tubular epithelial cells in vitro. J Nephrol 21, 931–940.
pubmed: 19034879
Wang, Y., Zheng, Y., and Li, W. (2021). Compression loading of osteoclasts attenuated microRNA-146a-5p expression, which promotes angiogenesis by targeting adiponectin. Sci China Life Sci, doi: https://doi.org/10.1007/s11427-020-1869-7 .
Wang, Z., Xu, Q., Zhang, N., Du, X., Xu, G., and Yan, X. (2020). CD146, from a melanoma cell adhesion molecule to a signaling receptor. Sig Transduct Target Ther 5, 148.
doi: 10.1038/s41392-020-00259-8
Wang, Z., and Yan, X. (2013). CD146, a multi-functional molecule beyond adhesion. Cancer Lett 330, 150–162.
pubmed: 23266426
doi: 10.1016/j.canlet.2012.11.049
Witmer, A. (2003). Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retinal Eye Res 22, 1–29.
doi: 10.1016/S1350-9462(02)00043-5
Wong, C. W., Yanagi, Y., Lee, W. K., Ogura, Y., Yeo, I., Wong, T.Y., and Cheung, C.M.G. (2016). Age-related macular degeneration and polypoidal choroidal vasculopathy in Asians. Prog Retinal Eye Res 53, 107–139.
doi: 10.1016/j.preteyeres.2016.04.002
Wu, Z., Liu, J., Chen, G., Du, J., Cai, H., Chen, X., Ye, G., Luo, Y., Luo, Y., Zhang, L., et al. (2021). CD146 is a novel ANGPTL2 receptor that promotes obesity by manipulating lipid metabolism and energy expenditure. Adv Sci 8, 2004032.
doi: 10.1002/advs.202004032
Xing, S., Luo, Y., Liu, Z., Bu, P., Duan, H., Liu, D., Wang, P., Yang, J., Song, L., Feng, J., et al. (2014). Targeting endothelial CD146 attenuates colitis and prevents colitis-associated carcinogenesis. Am J Pathol 184, 1604–1616.
pubmed: 24767106
doi: 10.1016/j.ajpath.2014.01.031
Yan, H., Zhang, C., Wang, Z., Tu, T., Duan, H., Luo, Y., Feng, J., Liu, F., and Yan, X. (2017). CD146 is required for VEGF-C-induced lymphatic sprouting during lymphangiogenesis. Sci Rep 7, 7442.
pubmed: 28785085
pmcid: 5547131
doi: 10.1038/s41598-017-06637-7
Yan, X., Lin, Y., Yang, D., Shen, Y., Yuan, M., Zhang, Z., Li, P., Xia, H., Li, L., Luo, D., et al. (2003). A novel anti-CD146 monoclonal antibody, AA98, inhibits angiogenesis and tumor growth. Blood 102, 184–191.
pubmed: 12609848
doi: 10.1182/blood-2002-04-1004
Yang, M., Li, S., Liu, W., Li, X., He, Y., Yang, Y., Sun, K., Zhang, L., Tian, W., Duan, L., et al. (2021). The ER membrane protein complex subunit Emc3 controls angiogenesis via the FZD4/WNT signaling axis. Sci China Life Sci, doi: https://doi.org/10.1007/s11427-021-1941-7 .
Ye, Z., Zhang, C., Tu, T., Sun, M., Liu, D., Lu, D., Feng, J., Yang, D., Liu, F., and Yan, X. (2013). Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension. Nat Commun 4, 2803.
pubmed: 24335906
doi: 10.1038/ncomms3803
Ylä-Herttuala, S., Rissanen, T.T., Vajanto, I., and Hartikainen, J. (2007). Vascular endothelial growth factors. J Am Coll Cardiol 49, 1015–1026.
pubmed: 17349880
doi: 10.1016/j.jacc.2006.09.053
Yoshioka, S., Fujiwara, H., Higuchi, T., Yamada, S., Maeda, M., and Fujii, S. (2003). Melanoma cell adhesion molecule (MCAM/CD146) is expressed on human luteinizing granulosa cells: enhancement of its expression by hCG, interleukin-1 and tumour necrosis factor-alpha. Mol Hum Reprod 9, 311–319.
pubmed: 12771231
doi: 10.1093/molehr/gag042
Zhang, L., Luo, Y., Teng, X., Wu, Z., Li, M., Xu, D., Wang, Q., Wang, F., Feng, J., Zeng, X., et al. (2018). CD146: a potential therapeutic target for systemic sclerosis. Protein Cell 9, 1050–1054.
pubmed: 29671201
pmcid: 6251808
doi: 10.1007/s13238-018-0531-x
Zheng, C., Qiu, Y., Zeng, Q., Zhang, Y., Lu, D., Yang, D., Feng, J., and Yan, X. (2009). Endothelial CD146 is required for in vitro tumor-induced angiogenesis: the role of a disulfide bond in signaling and dimerization. Int J Biochem Cell Biol 41, 2163–2172.
pubmed: 19782948
doi: 10.1016/j.biocel.2009.03.014
Zhou, H.J., Xu, Z., Wang, Z., Zhang, H., Zhuang, Z.W., Simons, M., and Min, W. (2018). SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis. Nat Commun 9, 3303.
pubmed: 30120232
pmcid: 6098000
doi: 10.1038/s41467-018-05812-2
Zhu, W., Shi, D.S., Winter, J.M., Rich, B.E., Tong, Z., Sorensen, L.K., Zhao, H., Huang, Y., Tai, Z., Mleynek, T.M., et al. (2017). Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy. J Clin Invest 127, 4569–4582.
pubmed: 29058688
pmcid: 5707163
doi: 10.1172/JCI91770