{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:30:04Z","timestamp":1784957404215,"version":"3.55.0"},"reference-count":66,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PRIN 2017XJ38A4"],"award-info":[{"award-number":["PRIN 2017XJ38A4"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003852","name":"Regione Campania","doi-asserted-by":"publisher","award":["Project SATIN - POR Campania FESR 2014\/2020"],"award-info":[{"award-number":["Project SATIN - POR Campania FESR 2014\/2020"]}],"id":[{"id":"10.13039\/501100003852","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Prolyl 3-hydroxylase 2 (P3H2) catalyzes the post-translational formation of 3-hydroxyproline on collagens, mainly on type IV. Its activity has never been directly associated to angiogenesis. Here, we identified P3H2 gene through a deep-sequencing transcriptome analysis of human umbilical vein endothelial cells (HUVECs) stimulated with vascular endothelial growth factor A (VEGF-A). Differently from many previous studies we carried out the stimulation not on starved HUVECs, but on cells grown to maintain the best condition for their in vitro survival and propagation. We showed that P3H2 is induced by VEGF-A in two primary human endothelial cell lines and that its transcription is modulated by VEGF-A\/VEGF receptor 2 (VEGFR-2) signaling pathway through p38 mitogen-activated protein kinase (MAPK). Then, we demonstrated that P3H2, through its activity on type IV Collagen, is essential for angiogenesis properties of endothelial cells in vitro by performing experiments of gain- and loss-of-function. Immunofluorescence studies showed that the overexpression of P3H2 induced a more condensed status of Collagen IV, accompanied by an alignment of the cells along the Collagen IV bundles, so towards an evident pro-angiogenic status. Finally, we found that P3H2 knockdown prevents pathological angiogenesis in vivo, in the model of laser-induced choroid neovascularization. Together these findings reveal that P3H2 is a new molecular player involved in new vessels formation and could be considered as a potential target for anti-angiogenesis therapy.<\/jats:p>","DOI":"10.3390\/ijms22083896","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T10:05:21Z","timestamp":1617962721000},"page":"3896","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Prolyl 3-Hydroxylase 2 Is a Molecular Player of Angiogenesis"],"prefix":"10.3390","volume":"22","author":[{"given":"Paola","family":"Pignata","sequence":"first","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Apicella","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Cicatiello","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1991-0082","authenticated-orcid":false,"given":"Caterina","family":"Puglisi","sequence":"additional","affiliation":[{"name":"IOM Ricerca s.r.l., 95029 Viagrande, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Magliacane Trotta","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5047-9713","authenticated-orcid":false,"given":"Remo","family":"Sanges","sequence":"additional","affiliation":[{"name":"Computational Genomics Laboratory, International School for Advanced Studies (SISSA), 34136 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6920-4402","authenticated-orcid":false,"given":"Valeria","family":"Tarallo","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6501-1697","authenticated-orcid":false,"given":"Sandro","family":"De Falco","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biophysics \u2018Adriano Buzzati-Traverso\u2019\u2014CNR, Angiogenesis LAB, 80131 Naples, Italy"},{"name":"ANBITION s.r.l., Department of R&amp;D, 80128 Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/nature10144","article-title":"Molecular mechanisms and clinical applications of angiogenesis","volume":"473","author":"Carmeliet","year":"2011","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"a006502","DOI":"10.1101\/cshperspect.a006502","article-title":"Signal transduction by vascular endothelial growth factor receptors","volume":"2","author":"Koch","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.mam.2011.04.004","article-title":"Vascular endothelial growth factors and receptors: Anti-angiogenic therapy in the treatment of cancer","volume":"32","author":"Tugues","year":"2011","journal-title":"Mol. Asp. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.biocel.2015.04.008","article-title":"The vascular endothelial growth factors and receptors family: Up to now the only target for anti-angiogenesis therapy","volume":"64","author":"Tarallo","year":"2015","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3904\/kjim.2014.29.1.1","article-title":"Antiangiogenesis therapy: An update after the first decade","volume":"29","year":"2014","journal-title":"Korean J. Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1136\/bjo.2006.113902","article-title":"Non-responders to bevacizumab (Avastin) therapy of choroidal neovascular lesions","volume":"91","author":"Lux","year":"2007","journal-title":"Br. J. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/nrc3366","article-title":"Controlling escape from angiogenesis inhibitors","volume":"12","author":"Sennino","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/eye.2013.107","article-title":"Adverse events and complications associated with intravitreal injection of anti-VEGF agents: A review of literature","volume":"27","author":"Falavarjani","year":"2013","journal-title":"Eye"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1023\/A:1009085422384","article-title":"Transcriptional profiling of human microvascular endothelial cells in the proliferative and quiescent state using cDNA arrays","volume":"3","author":"Zhang","year":"1999","journal-title":"Angiogenesis"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1023\/A:1016018617152","article-title":"cDNA microarray analysis of the gene expression profile of VEGF-activated human umbilical vein endothelial cells","volume":"4","author":"Abe","year":"2001","journal-title":"Angiogenesis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1023\/A:1016080321956","article-title":"Distinct regulation of genes by bFGF and VEGF-A in endothelial cells","volume":"4","author":"Jih","year":"2001","journal-title":"Angiogenesis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1096\/fj.00-0051com","article-title":"Differential expression of thymosin beta-10 by early passage and senescent vascular endothelium is modulated by VPF\/VEGF: Evidence for senescent endothelial cells in vivo at sites of atherosclerosis","volume":"15","author":"Vasile","year":"2001","journal-title":"FASEB J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1093\/molehr\/8.9.855","article-title":"Microarray analysis of VEGF-responsive genes in myometrial endothelial cells","volume":"8","author":"Weston","year":"2002","journal-title":"Mol. Hum. Reprod."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1161\/01.ATV.0000038995.31179.24","article-title":"Vascular endothelial growth factor-induced genes in human umbilical vein endothelial cells: Relative roles of KDR and Flt-1 receptors","volume":"22","author":"Yang","year":"2002","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/nm884","article-title":"Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1","volume":"9","author":"Autiero","year":"2003","journal-title":"Nat. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"19432","DOI":"10.1074\/jbc.M802973200","article-title":"Characterization of recombinant human prolyl 3-hydroxylase isoenzyme 2, an enzyme modifying the basement membrane Collagen IV","volume":"283","author":"Tiainen","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.bbrc.2004.03.060","article-title":"LEPREL1, a novel ER and Golgi resident member of the Leprecan family","volume":"317","author":"Jarnum","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"245","DOI":"10.3109\/03008207.2013.800867","article-title":"Collagen prolyl 3-hydroxylation: A major role for a minor post-translational modification?","volume":"54","author":"Hudson","year":"2013","journal-title":"Connect. Tissue Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1146\/annurev.biochem.77.032207.120833","article-title":"Collagen structure and stability","volume":"78","author":"Shoulders","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"25004","DOI":"10.1074\/jbc.274.35.25004","article-title":"Molecular characterization of a novel basement membrane-associated proteoglycan, leprecan","volume":"274","author":"McCarthy","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3576","DOI":"10.1038\/sj.onc.1203696","article-title":"Gros1, a potential growth suppressor on chromosome 1: Its identity to basement membrane-associated proteoglycan, leprecan","volume":"19","author":"Kaul","year":"2000","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/1523-1747.ep12598062","article-title":"Basement membranes: Structural and biosynthetic considerations","volume":"65","author":"Kefalides","year":"1975","journal-title":"J. Investig. Dermatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1021\/acs.jproteome.5b00767","article-title":"Comprehensive Characterization of Glycosylation and Hydroxylation of Basement Membrane Collagen IV by High-Resolution Mass Spectrometry","volume":"15","author":"Basak","year":"2016","journal-title":"J. Proteome Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1242\/jcs.73.1.19","article-title":"Extracellular matrix modulation of endothelial cell shape and motility following injury in vitro","volume":"73","author":"Young","year":"1985","journal-title":"J. Cell Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1083\/jcb.106.4.1365","article-title":"Differential effects of laminin, intact type IV collagen, and specific domains of type IV collagen on endothelial cell adhesion and migration","volume":"106","author":"Herbst","year":"1988","journal-title":"J. Cell Biol."},{"key":"ref_26","first-page":"18","article-title":"Matrix-driven cell size change modulates aortic endothelial cell proliferation and sheet migration","volume":"132","author":"Madri","year":"1988","journal-title":"Am. J. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1083\/jcb.97.1.153","article-title":"Capillary endothelial cell cultures: Phenotypic modulation by matrix components","volume":"97","author":"Madri","year":"1983","journal-title":"J. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1083\/jcb.107.4.1589","article-title":"Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures","volume":"107","author":"Kubota","year":"1988","journal-title":"J. Cell Biol."},{"key":"ref_29","first-page":"78","article-title":"The microvascular extracellular matrix. Developmental changes during angiogenesis in the aortic ring-plasma clot model","volume":"128","author":"Nicosia","year":"1987","journal-title":"Am. J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1290\/1071-2690(2000)036<0336:TICMAA>2.0.CO;2","article-title":"Type IV collagen modulates angiogenesis and neovessel survival in the rat aorta model","volume":"36","author":"Bonanno","year":"2000","journal-title":"In Vitro Cell Dev. Biol. Anim."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10456-013-9390-5","article-title":"Distinct roles of DKK1 and DKK2 in tumor angiogenesis","volume":"17","author":"Park","year":"2014","journal-title":"Angiogenesis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.mce.2013.04.024","article-title":"Stanniocalcin-1 and -2 promote angiogenic sprouting in HUVECs via VEGF\/VEGFR2 and angiopoietin signaling pathways","volume":"374","author":"Law","year":"2013","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.cell.2013.06.037","article-title":"Role of PFKFB3-driven glycolysis in vessel sprouting","volume":"154","author":"Georgiadou","year":"2013","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1128\/MCB.01038-07","article-title":"Sizn1 is a novel protein that functions as a transcriptional coactivator of bone morphogenic protein signaling","volume":"28","author":"Cho","year":"2008","journal-title":"Mol. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1006\/geno.1999.6087","article-title":"EHD2, EHD3, and EHD4 encode novel members of a highly conserved family of EH domain-containing proteins","volume":"63","author":"Pohl","year":"2000","journal-title":"Genomics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10456-009-9160-6","article-title":"Anti-angiogenic tyrosine kinase inhibitors: What is their mechanism of action?","volume":"13","author":"Gotink","year":"2010","journal-title":"Angiogenesis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e99","DOI":"10.1161\/RES.0000000000000054","article-title":"American Heart Association Council on Basic Cardiovascular, S.; Council on Cardiovascular, S.; Anesthesia, State-of-the-Art Methods for Evaluation of Angiogenesis and Tissue Vascularization: A Scientific Statement From the American Heart Association","volume":"116","author":"Simons","year":"2015","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.neuron.2012.06.018","article-title":"Mechanisms of age-related macular degeneration","volume":"75","author":"Ambati","year":"2012","journal-title":"Neuron"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6084","DOI":"10.1016\/j.febslet.2005.09.079","article-title":"Suppression of laser-induced choroidal neovascularization by oral administration of SA3443 in mice","volume":"579","author":"Muranaka","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nature06765","article-title":"Sequence- and target-independent angiogenesis suppression by siRNA via TLR3","volume":"452","author":"Kleinman","year":"2008","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1379\/1466-1268(2003)8<37:IVRFVA>2.0.CO;2","article-title":"Integrin alphavbeta3, requirement for VEGFR2-mediated activation of SAPK2\/p38 and for Hsp90-dependent phosphorylation of focal adhesion kinase in endothelial cells activated by VEGF","volume":"8","author":"Houle","year":"2003","journal-title":"Cell Stress Chaperones"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1084\/jem.20060807","article-title":"Integrin signaling is critical for pathological angiogenesis","volume":"203","author":"Mahabeleshwar","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1002\/ar.23567","article-title":"Basement Membrane Type IV Collagen and Laminin: An Overview of Their Biology and Value as Fibrosis Biomarkers of Liver Disease","volume":"300","author":"Mak","year":"2017","journal-title":"Anat. Rec."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2016.12.009","article-title":"The nature and biology of basement membranes","volume":"57\u201358","author":"Pozzi","year":"2017","journal-title":"Matrix Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2772","DOI":"10.1074\/jbc.M311901200","article-title":"Alpha(v)beta3 and alpha(v)beta5 integrins bind both the proximal RGD site and non-RGD motifs within noncollagenous (NC1) domain of the alpha3 chain of type IV collagen: Implication for the mechanism of endothelia cell adhesion","volume":"279","author":"Pedchenko","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1161\/01.RES.0000191547.64391.e3","article-title":"Endothelial extracellular matrix: Biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization","volume":"97","author":"Davis","year":"2005","journal-title":"Circ. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1161\/ATVBAHA.109.185165","article-title":"Mechanisms of vessel branching: Filopodia on endothelial tip cells lead the way","volume":"29","author":"Segura","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.mvr.2007.05.005","article-title":"Type IV collagen-derived angiogenesis inhibitors","volume":"74","author":"Mundel","year":"2007","journal-title":"Microvasc. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"30662","DOI":"10.1074\/jbc.M111.267906","article-title":"A role for prolyl 3-hydroxylase 2 in post-translational modification of fibril-forming collagens","volume":"286","author":"Fernandes","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4966","DOI":"10.1021\/bi00748a023","article-title":"Further hydroxylation of lysyl residues in collagen by protocollagen lysyl hydroxylase in vitro","volume":"12","author":"Kivirikko","year":"1973","journal-title":"Biochemistry"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1042\/bj1440115","article-title":"Activities of prolyl hydroxylase, lysyl hydroxylase, collagen galactosyltransferase and collagen glucosyltransferase in the liver of rats with hepatic injury","volume":"144","author":"Risteli","year":"1974","journal-title":"Biochem. J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1042\/bj1960683","article-title":"Regulation of collagen post-translational modification in transformed human and chick-embryo cells","volume":"196","author":"Myllyla","year":"1981","journal-title":"Biochem. J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1074\/jbc.M308181200","article-title":"The peptides acetyl-(Gly-3(S)Hyp-4(R)Hyp)10-NH2 and acetyl-(Gly-Pro-3(S)Hyp)10-NH2 do not form a collagen triple helix","volume":"279","author":"Mizuno","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6422","DOI":"10.1021\/ja034015j","article-title":"Effect of 3-hydroxyproline residues on collagen stability","volume":"125","author":"Jenkins","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"27566","DOI":"10.1074\/jbc.M602797200","article-title":"The crystal structure of a collagen-like polypeptide with 3(S)-hydroxyproline residues in the Xaa position forms a standard 7\/2 collagen triple helix","volume":"281","author":"Schumacher","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.ajhg.2011.08.003","article-title":"High myopia caused by a mutation in LEPREL1, encoding prolyl 3-hydroxylase 2","volume":"89","author":"Mordechai","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1111\/cge.12309","article-title":"Homozygous loss-of-function mutation of the LEPREL1 gene causes severe non-syndromic high myopia with early-onset cataract","volume":"86","author":"Guo","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8613","DOI":"10.1074\/jbc.M114.634915","article-title":"Post-translationally abnormal collagens of prolyl 3-hydroxylase-2 null mice offer a pathobiological mechanism for the high myopia linked to human LEPREL1 mutations","volume":"290","author":"Hudson","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1073\/pnas.1307597111","article-title":"Biological role of prolyl 3-hydroxylation in type IV collagen","volume":"111","author":"Pokidysheva","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"R97","DOI":"10.1093\/hmg\/dds346","article-title":"COL4A1 and COL4A2 mutations and disease: Insights into pathogenic mechanisms and potential therapeutic targets","volume":"21","author":"Kuo","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1093\/hmg\/ddi348","article-title":"Dominant mutations of Col4a1 result in basement membrane defects which lead to anterior segment dysgenesis and glomerulopathy","volume":"14","author":"McKie","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1093\/hmg\/ddm024","article-title":"Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis","volume":"16","author":"Gould","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1161\/CIRCULATIONAHA.114.013395","article-title":"Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention","volume":"131","author":"Jeanne","year":"2015","journal-title":"Circulation"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1136\/bjo.87.2.212","article-title":"Distribution of the Collagen IV isoforms in human Bruch\u2019s membrane","volume":"87","author":"Chen","year":"2003","journal-title":"Br. J. Ophthalmol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.matbio.2009.02.004","article-title":"Developmental distribution of Collagen IV isoforms and relevance to ocular diseases","volume":"28","author":"Bai","year":"2009","journal-title":"Matrix Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"18602","DOI":"10.1038\/srep18602","article-title":"Col4a1 mutations cause progressive retinal neovascular defects and retinopathy","volume":"6","author":"Alavi","year":"2016","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/3896\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:12:14Z","timestamp":1760364734000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/3896"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,9]]},"references-count":66,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22083896"],"URL":"https:\/\/doi.org\/10.3390\/ijms22083896","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,9]]}}}