Eyeing the Extracellular Matrix in Vascular Development and Microvascular Diseases and Bridging the Divide between Vascular Mechanics and Function

International Journal of Molecular Sciences - Tập 21 Số 10 - Trang 3487
Brahim Chaqour1,2, Charles Karrasch1
1Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA
2Department of Ophthalmology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA

Tóm tắt

The extracellular matrix (ECM) is critical in all aspects of vascular development and health: supporting cell anchorage, providing structure, organization and mechanical stability, and serving as a sink for growth factors and sustained survival signals. Abnormal changes in ECM protein expression, organization, and/or properties, and the ensuing changes in vascular compliance affect vasodilator responses, microvascular pressure transmission, and collateral perfusion. The changes in microvascular compliance are independent factors initiating, driving, and/or exacerbating a plethora of microvascular diseases of the eye including diabetic retinopathy (DR) and vitreoretinopathy, retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and neovascular glaucoma. Congruently, one of the major challenges with most vascular regenerative therapies utilizing localized growth factor, endothelial progenitor, or genetically engineered cell delivery, is the regeneration of blood vessels with physiological compliance properties. Interestingly, vascular cells sense physical forces, including the stiffness of their ECM, through mechanosensitive integrins, their associated proteins and the actomyosin cytoskeleton, which generates biochemical signals that culminate in a rapid expression of matricellular proteins such as cellular communication network 1 (CCN1) and CCN2 (aka connective tissue growth factor or CTGF). Loss or gain of function of these proteins alters genetic programs of cell growth, ECM biosynthesis, and intercellular signaling, that culminate in changes in cell behavior, polarization, and barrier function. In particular, the function of the matricellular protein CCN2/CTGF is critical during retinal vessel development and regeneration wherein new blood vessels form and invest a preformed avascular neural retina following putative gradients of matrix stiffness. These observations underscore the need for further in-depth characterization of the ECM-derived cues that dictate structural and functional properties of the microvasculature, along with the development of new therapeutic strategies addressing the ECM-dependent regulation of pathophysiological stiffening of blood vessels in ischemic retinopathies.

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Tài liệu tham khảo

Arjamaa, 2006, Oxygen-dependent diseases in the retina: Role of hypoxia-inducible factors, Exp. Eye Res., 83, 473, 10.1016/j.exer.2006.01.016

Stefansson, 2019, Retinal oximetry: Metabolic imaging for diseases of the retina and brain, Prog. Retin. Eye Res., 70, 1, 10.1016/j.preteyeres.2019.04.001

Yan, 2013, Cysteine-rich protein 61 (CCN1) and connective tissue growth factor (CCN2) at the crosshairs of ocular neovascular and fibrovascular disease therapy, J. Cell Commun. Signal., 7, 253, 10.1007/s12079-013-0206-6

Bek, 2013, Regional morphology and pathophysiology of retinal vascular disease, Prog. Retin. Eye Res., 36, 247, 10.1016/j.preteyeres.2013.07.002

Chirco, 2017, Structural and molecular changes in the aging choroid: Implications for age-related macular degeneration, Eye, 31, 10, 10.1038/eye.2016.216

Dewundara, 2019, Retinal and Choroidal Vascular Occlusion Following Aqueous Misdirection Syndrome in a Patient with Sickle Cell Trait, Retin. Cases Brief Rep., 13, 343, 10.1097/ICB.0000000000000590

Kinnunen, 2012, Vascular endothelial growth factors in retinal and choroidal neovascular diseases, Ann. Med., 44, 1, 10.3109/07853890.2010.532150

Hartnett, 2017, Diabetic retinopathy, an overview, Vision Res., 139, 1, 10.1016/j.visres.2017.07.006

Mohr, 2004, Potential new strategies to prevent the development of diabetic retinopathy, Expert Opin. Investig. Drugs, 13, 189, 10.1517/13543784.13.3.189

Krick, 2018, Recent clinically relevant highlights from the Diabetic Retinopathy Clinical Research Network, Curr. Opin. Ophthalmol., 29, 199, 10.1097/ICU.0000000000000472

Verges, 2016, Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory, J. Diabetes Res., 2016, 2156273

Whitehead, 2018, Diabetic retinopathy: A complex pathophysiology requiring novel therapeutic strategies, Expert Opin. Biol. Ther., 18, 1257, 10.1080/14712598.2018.1545836

Ebneter, 2016, Novelties in Diabetic Retinopathy, Endocr. Dev., 31, 84, 10.1159/000439391

Spijkerman, 2007, Endothelial dysfunction and low-grade inflammation and the progression of retinopathy in Type 2 diabetes, Diabet. Med., 24, 969, 10.1111/j.1464-5491.2007.02217.x

Kowluru, 2015, Oxidative stress and epigenetic modifications in the pathogenesis of diabetic retinopathy, Prog. Retin. Eye Res., 48, 40, 10.1016/j.preteyeres.2015.05.001

Chronopoulos, 2011, High glucose-induced altered basement membrane composition and structure increases trans-endothelial permeability: Implications for diabetic retinopathy, Curr. Eye Res., 36, 747, 10.3109/02713683.2011.585735

Bradley, 2007, Combination therapy for the treatment of ocular neovascularization, Angiogenesis, 10, 141, 10.1007/s10456-007-9069-x

Sapieha, 2010, Proliferative retinopathies: Angiogenesis that blinds, Int. J. Biochem. Cell Biol., 42, 5, 10.1016/j.biocel.2009.10.006

Smith, 2010, Prediction of diabetic retinopathy: Role of oxidative stress and relevance of apoptotic biomarkers, EPMA J., 1, 56, 10.1007/s13167-010-0002-9

Chen, 2011, Wnt signaling mediates pathological vascular growth in proliferative retinopathy, Circulation, 124, 1871, 10.1161/CIRCULATIONAHA.111.040337

Bressler, N.M., Beaulieu, W.T., Bressler, S.B., Glassman, A.R., Melia, B.M., Jampol, L.M., Jhaveri, C.D., Salehi-Had, H., Velez, G., and Sun, J.K. (2019). Anti-Vascular Endothelial Growth Factor Therapy and Risk of Traction Retinal Detachment in Eyes with Proliferative Diabetic Retinopathy: Pooled Analysis of Five DRCR Retina Network Randomized Clinical Trials. Retina.

2017, The Blood-Retinal Barrier in the Management of Retinal Disease: EURETINA Award Lecture, Ophthalmologica, 237, 1, 10.1159/000455809

Mantelli, 2014, NGF and VEGF effects on retinal ganglion cell fate: New evidence from an animal model of diabetes, Eur. J. Ophthalmol., 24, 247, 10.5301/ejo.5000359

Mansour, 2020, The Evolving Treatment of Diabetic Retinopathy, Clin. Ophthalmol., 14, 653, 10.2147/OPTH.S236637

Birukova, 2013, Endothelial barrier disruption and recovery is controlled by substrate stiffness, Microvasc. Res., 87, 50, 10.1016/j.mvr.2012.12.006

Lampi, M.C., and Reinhart-King, C.A. (2018). Targeting extracellular matrix stiffness to attenuate disease: From molecular mechanisms to clinical trials. Sci. Transl. Med., 10.

Chaqour, B. (2019). Caught between a “Rho” and a hard place: Are CCN1/CYR61 and CCN2/CTGF the arbiters of microvascular stiffness?. J. Cell Commun. Signal.

Hoefer, 2013, Biomechanical factors as triggers of vascular growth, Cardiovasc. Res., 99, 276, 10.1093/cvr/cvt089

Gkretsi, 2018, Cell Adhesion and Matrix Stiffness: Coordinating Cancer Cell Invasion and Metastasis, Front. Oncol., 8, 145, 10.3389/fonc.2018.00145

Klein, 2009, Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening, Curr. Biol., 19, 1511, 10.1016/j.cub.2009.07.069

Laurent, 2005, Structural and genetic bases of arterial stiffness, Hypertension, 45, 1050, 10.1161/01.HYP.0000164580.39991.3d

Nasrollahi, 2017, Past matrix stiffness primes epithelial cells and regulates their future collective migration through a mechanical memory, Biomaterials, 146, 146, 10.1016/j.biomaterials.2017.09.012

Aragona, 2013, A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors, Cell, 154, 1047, 10.1016/j.cell.2013.07.042

Chintala, 2012, Connective tissue growth factor regulates retinal neovascularization through p53 protein-dependent transactivation of the matrix metalloproteinase (MMP)-2 gene, J. Biol. Chem., 287, 40570, 10.1074/jbc.M112.386565

Hausman, 2007, Ocular extracellular matrices in development, Prog. Retin. Eye Res., 26, 162, 10.1016/j.preteyeres.2006.11.001

Dewing, J.M., Carare, R.O., Lotery, A.J., and Ratnayaka, J.A. (2019). The Diverse Roles of TIMP-3: Insights into Degenerative Diseases of the Senescent Retina and Brain. Cells, 9.

Lau, 2013, Pathophysiology of the brain extracellular matrix: A new target for remyelination, Nat. Rev. Neurosci., 14, 722, 10.1038/nrn3550

Punal, 2017, Astrocytes follow ganglion cell axons to establish an angiogenic template during retinal development, Glia, 65, 1697, 10.1002/glia.23189

Sapieha, 2008, The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis, Nat. Med., 14, 1067, 10.1038/nm.1873

Fu, Z., Sun, Y., Cakir, B., Tomita, Y., Huang, S., Wang, Z., Liu, C.H., Steve, S.C., Britton, W., and Timothy, S.K. (2020). Targeting Neurovascular Interaction in Retinal Disorders. Int. J. Mol. Sci., 21.

Adair, 1990, Growth regulation of the vascular system: Evidence for a metabolic hypothesis, Am. J. Physiol., 259, R393

Liu, 2017, Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis, Nat. Commun., 8, 584, 10.1038/s41467-017-00551-2

Du, 2017, Unique patterns of organization and migration of FGF-expressing cells during Drosophila morphogenesis, Dev. Biol., 427, 35, 10.1016/j.ydbio.2017.05.009

Ingber, 2002, Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology, Circ. Res., 91, 877, 10.1161/01.RES.0000039537.73816.E5

Hunter, 2019, CNS synapses are stabilized trans-synaptically by laminins and laminin-interacting proteins, J. Comp. Neurol., 527, 67, 10.1002/cne.24338

Bringmann, 2006, Muller cells in the healthy and diseased retina, Prog. Retin. Eye Res., 25, 397, 10.1016/j.preteyeres.2006.05.003

Vecino, 2016, Glia-neuron interactions in the mammalian retina, Prog. Retin. Eye Res., 51, 1, 10.1016/j.preteyeres.2015.06.003

Nishikiori, 2007, Glial cell-derived cytokines attenuate the breakdown of vascular integrity in diabetic retinopathy, Diabetes, 56, 1333, 10.2337/db06-1431

Shen, 2012, Conditional Mullercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model, J. Neurosci., 32, 15715, 10.1523/JNEUROSCI.2841-12.2012

Moon, S., Lee, S., Caesar, J., Pruchenko, S., Leask, A., Knowles, J.A., Sinon, J., and Chaqour, B. (2020). A CTGF-YAP regulatory pathway is essential for angiogenesis and barriergenesis in the retina. iScience, in press.

Yurchenco, 2004, Basement membrane assembly, stability and activities observed through a developmental lens, Matrix Biol., 22, 521, 10.1016/j.matbio.2003.10.006

Yurchenco, P.D. (2011). Basement membranes: Cell scaffoldings and signaling platforms. Cold Spring Harb. Perspect. Biol., 3.

Poschl, 2004, Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development, Development, 131, 1619, 10.1242/dev.01037

Gould, 2005, Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly, Science, 308, 1167, 10.1126/science.1109418

Hannocks, 2017, Vascular laminins in physiology and pathology, Matrix Biol., 57–58, 140

Wallquist, 2005, Impeded interaction between Schwann cells and axons in the absence of laminin alpha4, J. Neurosci., 25, 3692, 10.1523/JNEUROSCI.5225-04.2005

Thomsen, 2017, The vascular basement membrane in the healthy and pathological brain, J. Cereb. Blood Flow Metab., 37, 3300, 10.1177/0271678X17722436

Kunze, 2010, Deposition of nidogens and other basement membrane proteins in the young and aging mouse retina, Ophthalmic Res., 43, 108, 10.1159/000247595

Bader, 2005, Compound genetic ablation of nidogen 1 and 2 causes basement membrane defects and perinatal lethality in mice, Mol. Cell Biol., 25, 6846, 10.1128/MCB.25.15.6846-6856.2005

Vempati, P., Popel, A.S., and Mac, G.F. (2011). Formation of VEGF isoform-specific spatial distributions governing angiogenesis: Computational analysis. BMC Syst. Biol., 5.

Bishop, 2015, The role of extracellular matrix in retinal vascular development and preretinal neovascularization, Exp. Eye Res., 133, 30, 10.1016/j.exer.2014.10.021

Bornstein, 2000, Thrombospondin 2 modulates collagen fibrillogenesis and angiogenesis, J. Investig. Dermatol. Symp. Proc., 5, 61, 10.1046/j.1087-0024.2000.00005.x

Bradshaw, 2009, The role of SPARC in extracellular matrix assembly, J. Cell Commun. Signal., 3, 239, 10.1007/s12079-009-0062-6

Halfter, 1998, Collagen XVIII is a basement membrane heparan sulfate proteoglycan, J. Biol. Chem., 273, 25404, 10.1074/jbc.273.39.25404

Sullivan, 2006, Matricellular hevin regulates decorin production and collagen assembly, J. Biol. Chem., 281, 27621, 10.1074/jbc.M510507200

Chaqour, 2013, Molecular control of vascular development by the matricellular proteins CCN1 (Cyr61) and CCN2 (CTGF), Trends Dev. Biol., 7, 59

Bornstein, 2002, Matricellular proteins: Extracellular modulators of cell function, Curr. Opin. Cell Biol., 14, 608, 10.1016/S0955-0674(02)00361-7

Yang, 2000, Matricellular proteins as modulators of cell-matrix interactions: Adhesive defect in thrombospondin 2-null fibroblasts is a consequence of increased levels of matrix metalloproteinase-2, Mol. Biol. Cell, 11, 3353, 10.1091/mbc.11.10.3353

Praidou, 2010, Angiogenic growth factors and their inhibitors in diabetic retinopathy, Curr. Diabetes Rev., 6, 304, 10.2174/157339910793360815

Spirin, 1999, Basement membrane and growth factor gene expression in normal and diabetic human retinas, Curr. Eye Res., 18, 490, 10.1076/ceyr.18.6.490.5267

Chintala, 2015, The matricellular protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling, Development, 142, 2364

Krupska, 2015, Eyeing the Cyr61/CTGF/NOV (CCN) group of genes in development and diseases: Highlights of their structural likenesses and functional dissimilarities, Hum Genomics, 9, 24, 10.1186/s40246-015-0046-y

Sage, 1994, Regulation of angiogenesis by extracellular matrix: The growth and the glue, J. Hypertens. Suppl., 12, S145

Choi, 2013, Degradome products of the matricellular protein CCN1 as modulators of pathological angiogenesis in the retina, J. Biol. Chem., 288, 23075, 10.1074/jbc.M113.475418

Mo, 2006, The matricellular protein CCN1 is essential for cardiac development, Circ. Res., 99, 961, 10.1161/01.RES.0000248426.35019.89

Perbal, 2018, The official unified nomenclature adopted by the HGNC calls for the use of the acronyms, CCN1-6, and discontinuation in the use of CYR61, CTGF, NOV and WISP 1-3 respectively, J. Cell Commun. Signal., 12, 625, 10.1007/s12079-018-0491-1

Zhang, Y. (2008). I-TASSER server for protein 3D structure prediction. BMC Bioinform., 9.

Chowdhury, 2004, Regulation of connective tissue growth factor (CTGF/CCN2) gene transcription and mRNA stability in smooth muscle cells. Involvement of RhoA GTPase and p38 MAP kinase and sensitivity to actin dynamics, Eur. J. Biochem., 271, 4436, 10.1111/j.1432-1033.2004.04382.x

Hall-Glenn, F., De Young, R.A., Huang, B.L., van Handel, B., Hofmann, J.J., Chen, T.T., Choi, A., Ong, J.R., Benya, P.D., and Mikkola, H. (2012). CCN2/connective tissue growth factor is essential for pericyte adhesion and endothelial basement membrane formation during angiogenesis. PLoS ONE, 7.

Katsube, 2009, Role of CCN, a vertebrate specific gene family, in development, Dev. Growth Differ, 51, 55, 10.1111/j.1440-169X.2009.01077.x

Chaqour, 2006, Mechanical stretch modulates the promoter activity of the profibrotic factor CCN2 through increased actin polymerization and NF-kappaB activation, J. Biol. Chem., 281, 20608, 10.1074/jbc.M600214200

Biros, 2014, Differential gene expression in the proximal neck of human abdominal aortic aneurysm, Atherosclerosis, 233, 211, 10.1016/j.atherosclerosis.2013.12.017

Zhao, 2017, The status of pulmonary fibrosis in systemic sclerosis is associated with IRF5, STAT4, IRAK1, and CTGF polymorphisms, Rheumatol. Int., 37, 1303, 10.1007/s00296-017-3722-5

Wang, 2010, Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes, J. Med. Genet., 47, 391, 10.1136/jmg.2009.073098

Gaudreault, 2011, Replication of genetic association studies in aortic stenosis in adults, Am. J. Cardiol., 108, 1305, 10.1016/j.amjcard.2011.06.050

Donlon, 2017, Association of Polymorphisms in Connective Tissue Growth Factor and Epidermal Growth Factor Receptor Genes With Human Longevity, J. Gerontol. A Biol. Sci. Med. Sci., 72, 1038

Feijen, 2004, Connective tissue growth factor expression and Smad signaling during mouse heart development and myocardial infarction, Dev. Dyn., 231, 542, 10.1002/dvdy.20162

Frost, 2018, Multiple enhancer regions govern the transcription of CCN2 during embryonic development, J. Cell Commun. Signal., 12, 231, 10.1007/s12079-017-0440-4

Li, 2015, Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (Review), Int. J. Mol. Med., 36, 1451, 10.3892/ijmm.2015.2390

Trost, 2016, Immunohistochemical Detection of CTGF in the Human Eye, Curr. Eye Res., 41, 1571, 10.3109/02713683.2016.1143014

Watanabe, 2005, Expression of connective tissue growth factor and its potential role in choroidal neovascularization, Retina, 25, 911, 10.1097/00006982-200510000-00015

Mann, 2017, Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer’s disease, Nat. Commun., 8, 1403, 10.1038/s41467-017-01096-0

Ivkovic, 2003, Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development, Development, 130, 2779, 10.1242/dev.00505

Kablar, 2008, Pulmonary hypoplasia in the connective tissue growth factor (Ctgf) null mouse, Dev. Dyn., 237, 485, 10.1002/dvdy.21433

Toda, 2017, Crucial Role of Mesangial Cell-derived Connective Tissue Growth Factor in a Mouse Model of Anti-Glomerular Basement Membrane Glomerulonephritis, Sci. Rep., 7, 42114, 10.1038/srep42114

Almendral, 1988, Complexity of the early genetic response to growth factors in mouse fibroblasts, Mol. Cell Biol., 8, 2140

Bradham, 1991, Connective tissue growth factor: A cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10, J. Cell Biol., 114, 1285, 10.1083/jcb.114.6.1285

Grotendorst, 1996, A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene, Cell Growth Differ., 7, 469

Chaqour, 2006, Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins, FEBS J., 273, 3639, 10.1111/j.1742-4658.2006.05360.x

Hanna, 2009, Mechanical regulation of the proangiogenic factor CCN1/CYR61 gene requires the combined activities of MRTF-A and CREB-binding protein histone acetyltransferase, J. Biol. Chem., 284, 23125, 10.1074/jbc.M109.019059

Yan, 2015, Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia, J. Biol. Chem., 290, 23264, 10.1074/jbc.M115.646950

Muratoglu, 2013, LRP1 protects the vasculature by regulating levels of connective tissue growth factor and HtrA1, Arterioscler. Thromb. Vasc. Biol., 33, 2137, 10.1161/ATVBAHA.113.301893

Beaumont, 2017, Mechanisms underlying the cardiac antifibrotic effects of losartan metabolites, Sci. Rep., 7, 41865, 10.1038/srep41865

Zhang, 2019, Knockdown of FOXM1 inhibits activation of keloid fibroblasts and extracellular matrix production via inhibition of TGF-beta1/Smad pathway, Life Sci., 232, 116637, 10.1016/j.lfs.2019.116637

Kubota, 2015, Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions, Clin. Sci., 128, 181, 10.1042/CS20140264

Branchetti, 2013, Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm, Cardiovasc. Res., 100, 316, 10.1093/cvr/cvt205

Jun, 2011, Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets, Nat. Rev. Drug Discov., 10, 945, 10.1038/nrd3599

Suzuma, 2000, Vascular endothelial growth factor induces expression of connective tissue growth factor via KDR, Flt1, and phosphatidylinositol 3-kinase-akt-dependent pathways in retinal vascular cells, J. Biol. Chem., 275, 40725, 10.1074/jbc.M006509200

Brigstock, 2010, Connective tissue growth factor (CCN2, CTGF) and organ fibrosis: Lessons from transgenic animals, J. Cell Commun. Signal., 4, 1, 10.1007/s12079-009-0071-5

Kular, 2011, The CCN family: A new class of inflammation modulators?, Biochimie, 93, 377, 10.1016/j.biochi.2010.11.010

Villacorta, 2003, Alpha-tocopherol induces expression of connective tissue growth factor and antagonizes tumor necrosis factor-alpha-mediated downregulation in human smooth muscle cells, Circ. Res., 92, 104, 10.1161/01.RES.0000049103.38175.1B

Ramazani, 2018, Connective tissue growth factor (CTGF) from basics to clinics, Matrix Biol., 68–69, 44, 10.1016/j.matbio.2018.03.007

Sarnicola, 2019, Fuchs Endothelial Corneal Dystrophy: Update on Pathogenesis and Future Directions, Eye Contact Lens, 45, 1, 10.1097/ICL.0000000000000469

Sun, 2020, Resolvin D1 suppresses pannus formation via decreasing connective tissue growth factor caused by upregulation of miRNA-146a-5p in rheumatoid arthritis, Arthritis Res. Ther., 22, 61, 10.1186/s13075-020-2133-2

Lim, 2019, Targeting the highly abundant circular RNA circSlc8a1 in cardiomyocytes attenuates pressure overload induced hypertrophy, Cardiovasc. Res., 115, 1998, 10.1093/cvr/cvz130

Zheng, 2018, lncRNA PVT1 promotes the angiogenesis of vascular endothelial cell by targeting miR26b to activate CTGF/ANGPT2, Int. J. Mol. Med., 42, 489

Lau, 2016, Cell surface receptors for CCN proteins, J. Cell Commun. Signal., 10, 121, 10.1007/s12079-016-0324-z

Butler, 2008, Pharmacoproteomics of a metalloproteinase hydroxamate inhibitor in breast cancer cells: Dynamics of membrane type 1 matrix metalloproteinase-mediated membrane protein shedding, Mol. Cell Biol., 28, 4896, 10.1128/MCB.01775-07

Gao, 2003, Low density lipoprotein receptor-related protein (LRP) is a heparin-dependent adhesion receptor for connective tissue growth factor (CTGF) in rat activated hepatic stellate cells, Hepatol. Res., 27, 214, 10.1016/S1386-6346(03)00241-9

Oikonomopoulou, 2011, Kallikrein-related peptidase 12 hydrolyzes matricellular proteins of the CCN family and modifies interactions of CCN1 and CCN5 with growth factors, J. Biol. Chem., 286, 25505, 10.1074/jbc.M110.213231

Chen, 2010, Structural and functional insights into the TEAD-YAP complex in the Hippo signaling pathway, Protein Cell, 1, 1073, 10.1007/s13238-010-0138-3

Leask, 2006, All in the CCN family: Essential matricellular signaling modulators emerge from the bunker, J. Cell Sci., 119, 4803, 10.1242/jcs.03270

Leask, 2008, Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis, Cytokine Growth Factor Rev., 19, 133, 10.1016/j.cytogfr.2008.01.002

Graness, 2006, STAT3-independent inhibition of lysophosphatidic acid-mediated upregulation of connective tissue growth factor (CTGF) by cucurbitacin I, Biochem. Pharmacol., 72, 32, 10.1016/j.bcp.2006.04.001

Ball, 2003, The heparin-binding 10 kDa fragment of connective tissue growth factor (CTGF) containing module 4 alone stimulates cell adhesion, J. Endocrinol., 176, R1, 10.1677/joe.0.176r001

Mokalled, 2016, Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish, Science, 354, 630, 10.1126/science.aaf2679

Hinton, 2004, Accumulation of NH2-terminal fragment of connective tissue growth factor in the vitreous of patients with proliferative diabetic retinopathy, Diabetes Care, 27, 758, 10.2337/diacare.27.3.758

Yoon, 2010, The opposing effects of CCN2 and CCN5 on the development of cardiac hypertrophy and fibrosis, J. Mol. Cell Cardiol., 49, 294, 10.1016/j.yjmcc.2010.04.010

Kaasboll, 2018, Connective tissue growth factor (CCN2) is a matricellular preproprotein controlled by proteolytic activation, J. Biol. Chem., 293, 17953, 10.1074/jbc.RA118.004559

King, 2013, Vascular complications of diabetes: Mechanisms of injury and protective factors, Cell Metab., 17, 20, 10.1016/j.cmet.2012.11.012

Hughes, 2007, Advanced glycation end products cause increased CCN family and extracellular matrix gene expression in the diabetic rodent retina, Diabetologia, 50, 1089, 10.1007/s00125-007-0621-4

Twigg, 2018, Regulation and bioactivity of the CCN family of genes and proteins in obesity and diabetes, J. Cell Commun. Signal., 12, 359, 10.1007/s12079-018-0458-2

Singh, 2018, Type 1 diabetes mellitus induces structural changes and molecular remodelling in the rat kidney, Mol. Cell Biochem., 449, 9, 10.1007/s11010-018-3338-4

Klaassen, 2015, The role of CTGF in diabetic retinopathy, Exp. Eye Res., 133, 37, 10.1016/j.exer.2014.10.016

Kuiper, 2007, Angiogenesis is not impaired in connective tissue growth factor (CTGF) knock-out mice, J. Histochem. Cytochem., 55, 1139, 10.1369/jhc.7A7258.2007

Schouten, 2015, New ophthalmologic imaging techniques for detection and monitoring of neurodegenerative changes in diabetes: A systematic review, Lancet Diabetes Endocrinol., 3, 653, 10.1016/S2213-8587(15)00136-9

Tikellis, 2004, Connective tissue growth factor is up-regulated in the diabetic retina: Amelioration by angiotensin-converting enzyme inhibition, Endocrinology, 145, 860, 10.1210/en.2003-0967

McClain, 2009, Increased MMP-3 and CTGF expression during lipopolysaccharide-induced dopaminergic neurodegeneration, Neurosci. Lett., 460, 27, 10.1016/j.neulet.2009.05.044

Jadhav, V., Luo, Q., Dominguez, J.M., Al-Sabah, J., Chaqour, B., Grant, M.B., and Bhatwadekar, A.D. (2016). Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF). PLoS ONE, 11.

Kuiper, E.J., van Nieuwenhoven, F.A., de Smet, M.D., van Meurs, J.C., Tanck, M.W., Oliver, N., Klaassen, I., Van Noorden, C.J., Goldschmeding, R., and Schlingemann, R.O. (2008). The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy. PLoS ONE, 3.

Doherty, H.E., Kim, H.S., Hiller, S., Sulik, K.K., and Maeda, N. (2010). A mouse strain where basal connective tissue growth factor gene expression can be switched from low to high. PLoS ONE, 5.

Dean, 2007, Identification of candidate angiogenic inhibitors processed by matrix metalloproteinase 2 (MMP-2) in cell-based proteomic screens: Disruption of vascular endothelial growth factor (VEGF)/heparin affin regulatory peptide (pleiotrophin) and VEGF/Connective tissue growth factor angiogenic inhibitory complexes by MMP-2 proteolysis, Mol. Cell Biol., 27, 8454, 10.1128/MCB.00821-07

Ishikawa, 2016, Molecular mechanisms of subretinal fibrosis in age-related macular degeneration, Exp. Eye Res., 142, 19, 10.1016/j.exer.2015.03.009

Harada, 2006, The role of cytokines and trophic factors in epiretinal membranes: Involvement of signal transduction in glial cells, Prog. Retin. Eye Res., 25, 149, 10.1016/j.preteyeres.2005.09.001

Kadhim, 2016, Classifications for Proliferative Vitreoretinopathy (PVR): An Analysis of Their Use in Publications over the Last 15 Years, J. Ophthalmol., 2016, 7807596

Cui, 2007, Stage specificity of novel growth factor expression during development of proliferative vitreoretinopathy, Eye, 21, 200, 10.1038/sj.eye.6702169

Hinton, 2002, Novel growth factors involved in the pathogenesis of proliferative vitreoretinopathy, Eye, 16, 422, 10.1038/sj.eye.6700190

Guo, 2009, Modulation of migration and Ca2+ signaling in retinal pigment epithelium cells by recombinant human CTGF, Curr. Eye Res., 34, 852, 10.3109/02713680903128935

Roy, 2016, Retinal fibrosis in diabetic retinopathy, Exp. Eye Res., 142, 71, 10.1016/j.exer.2015.04.004

Miller, 2013, Vascular endothelial growth factor a in intraocular vascular disease, Ophthalmology, 120, 106, 10.1016/j.ophtha.2012.07.038

Freiberg, 2019, Microvascular abnormalities secondary to radiation therapy in neovascular age-related macular degeneration: Findings from the INTREPID clinical trial, Br. J. Ophthalmol., 103, 469, 10.1136/bjophthalmol-2018-311865

Thach, 2016, Cellular and Molecular Pathology of Age-Related Macular Degeneration: Potential Role for Proteoglycans, J. Ophthalmol., 2016, 2913612

He, 2008, Connective tissue growth factor as a mediator of intraocular fibrosis, Investig. Ophthalmol. Vis. Sci., 49, 4078, 10.1167/iovs.07-1302

Daftarian, 2019, Effects of intravitreal connective tissue growth factor neutralizing antibody on choroidal neovascular membrane-associated subretinal fibrosis, Exp. Eye Res., 184, 286, 10.1016/j.exer.2019.04.027

Ibrahim, 2016, Hyperhomocysteinemia disrupts retinal pigment epithelial structure and function with features of age-related macular degeneration, Oncotarget, 7, 8532, 10.18632/oncotarget.7384

Verwoert, 2018, Involvement of the ubiquitin-proteasome system in the expression of extracellular matrix genes in retinal pigment epithelial cells, Biochem. Biophys. Rep., 13, 83

Caballero, S., Yang, R., Grant, M.B., and Chaqour, B. (2010). Selective Blockade of Cytoskeletal Actin Remodeling Reduces Experimental Choroidal Neovascularization. Investig. Ophthalmol. Vis. Sci.

Quigley, 2011, Glaucoma, Lancet, 377, 1367, 10.1016/S0140-6736(10)61423-7

Reinehr, 2019, Loss of retinal ganglion cells in a new genetic mouse model for primary open-angle glaucoma, J. Cell Mol. Med., 23, 5497, 10.1111/jcmm.14433

Mietzner, 2019, Causative glaucoma treatment: Promising targets and delivery systems, Drug Discov. Today, 24, 1606, 10.1016/j.drudis.2019.03.017

Braunger, 2015, The aqueous humor outflow pathways in glaucoma: A unifying concept of disease mechanisms and causative treatment, Eur. J. Pharm. Biopharm., 95, 173, 10.1016/j.ejpb.2015.04.029

Kuespert, 2015, The regulation of connective tissue growth factor expression influences the viability of human trabecular meshwork cells, J. Cell Mol. Med., 19, 1010, 10.1111/jcmm.12492

Hamon, 2019, Linking YAP to Muller Glia Quiescence Exit in the Degenerative Retina, Cell Rep., 27, 1712, 10.1016/j.celrep.2019.04.045

Goldman, 2014, Muller glial cell reprogramming and retina regeneration, Nat. Rev. Neurosci., 15, 431, 10.1038/nrn3723

Medeiros, 2018, The Corneal Basement Membranes and Stromal Fibrosis, Investig. Ophthalmol. Vis. Sci., 59, 4044, 10.1167/iovs.18-24428

Gibson, 2014, Conditional knockout of CTGF affects corneal wound healing, Investig. Ophthalmol. Vis. Sci., 55, 2062, 10.1167/iovs.13-12735

Feng, X., Pi, L., Sriram, S., Schultz, G.S., and Gibson, D.J. (2017). Connective tissue growth factor is not necessary for haze formation in excimer laser wounded mouse corneas. PLoS ONE, 12.

Matthaei, 2019, Fuchs Endothelial Corneal Dystrophy: Clinical, Genetic, Pathophysiologic, and Therapeutic Aspects, Annu. Rev. Vis. Sci., 5, 151, 10.1146/annurev-vision-091718-014852

Chung, 2014, Functional impact of ZEB1 mutations associated with posterior polymorphous and Fuchs’ endothelial corneal dystrophies, Investig. Ophthalmol. Vis. Sci., 55, 6159, 10.1167/iovs.14-15247