{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T16:26:29Z","timestamp":1773937589295,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,17]]},"group-title":"Developmental Biology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Pericytes, specialized mural cells of capillaries, fulfill crucial physiological functions including promoting endothelial barrier function and regulating angiogenesis. Pericyte loss or dysfunction represents a central pathological feature in diabetic retinopathy (DR) and is increasingly recognized in neurodegenerative diseases as well as in poor stroke outcomes, underscoring an urgent need for therapies that restore pericyte function or promote their regeneration. Here, we utilized a Frizzled4 (FZD4) and Low-Density Lipoprotein Receptor\u2013Related Protein 5 (LRP5) agonist antibody (F4L5.13) to investigate the functional consequences of mimicking \u03b2-catenin-dependent signaling in CNS endothelial cells (ECs), which is physiologically induced by Norrin or WNT7A\/B. In platelet-derived growth factor subunit B (\n                  <jats:italic>Pdgfb)<\/jats:italic>\n                  EC-specific knockout (ECKO) mice, a model of severe developmental pericyte deficiency with secondary blood-retina barrier (BRB) defects and hemorrhages, F4L5.13 significantly promoted retinal pericyte\/mural cell proliferation and coverage, improved BRB function, reduced hemorrhages, and normalized vascular morphology. F4L5.13 restored\n                  <jats:italic>Pdgfb<\/jats:italic>\n                  mRNA expression levels from non-recombined cells in\n                  <jats:italic>Pdgfb<\/jats:italic>\n                  ECKO retinas. These findings highlight interactions of \u03b2-catenin-dependent signaling and PDGFB production, identify a key pharmacodynamic action of F4L5.13 distinct from anti-VEGF therapies, and suggest that FZD4\/LRP5 agonists may have uses as a regenerative pharmacology approach that promotes pericyte coverage in the neurovascular unit.\n                <\/jats:p>","DOI":"10.64898\/2026.03.13.711629","type":"posted-content","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T13:25:13Z","timestamp":1773753913000},"source":"Crossref","is-referenced-by-count":0,"title":["A FZD4\/LRP5 agonist restores pericyte coverage and vascular integrity by increasing PDGFB signaling"],"prefix":"10.64898","author":[{"given":"Jacklyn","family":"Levey","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Neuroscience, University of Minnesota Medical School, Twin Cities, Minneapolis, MN, United States"},{"name":"University of Minnesota, Graduate Program in Molecular, Cellular, and Developmental Biology, and Genetics, Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miranda","family":"Howe","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Neuroscience, University of Minnesota Medical School, Twin Cities, Minneapolis, MN, United States"},{"name":"University of Minnesota, Graduate Program in Molecular, Cellular, and Developmental Biology, and Genetics, Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaia","family":"Douglas","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Neuroscience, University of Minnesota Medical School, Twin Cities, Minneapolis, MN, United States"},{"name":"Eppley Institute, University of Nebraska Medical Center, Omaha, NE"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel","family":"Odame","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Neuroscience, University of Minnesota Medical School, Twin Cities, Minneapolis, MN, United States"},{"name":"University of Minnesota, Graduate Program in Molecular, Cellular, and Developmental Biology, and Genetics, Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neal","family":"Rajvansh","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Neuroscience, University of Minnesota Medical School, Twin Cities, Minneapolis, MN, United States"},{"name":"University of Wisconsin-Madison, Undergraduate Department of Neurobiology, Madison, WI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ha-Neul","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Neuroscience, University of Minnesota Medical School, Twin Cities, Minneapolis, MN, United States"},{"name":"University of Minnesota, Graduate Program in Molecular, Cellular, and Developmental Biology, and Genetics, Minneapolis, MN"},{"name":"University of Colorado Anschutz Medical Campus, Department of Pharmacology, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Neuroscience, University of Minnesota Medical School, Twin Cities, Minneapolis, MN, United States"},{"name":"Department of Biology, StThomas University, StPaul, MN, USA,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Neuroscience, University of Minnesota Medical School, Twin Cities, Minneapolis, MN, United States"},{"name":"Chicago College of Osteopathic Medicine, Chicago, IL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heidi","family":"Roehrich","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Neuroscience, University of Minnesota Medical School, Twin Cities, Minneapolis, MN, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Somasekar","family":"Seshagiri","sequence":"additional","affiliation":[{"name":"AntlerA Therapeutics, Foster City, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7241-9044","authenticated-orcid":false,"given":"Stephane","family":"Angers","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Toronto, Toronto, ON, Canada"},{"name":"Terrence Donnelly Centre for Cellular and Biomolecular Research, Toronto, ON, Canada"},{"name":"Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2458-6010","authenticated-orcid":false,"given":"Harald J.","family":"Junge","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Neuroscience, University of Minnesota Medical School, Twin Cities, Minneapolis, MN, United States"},{"name":"University of Minnesota, Graduate Program in Molecular, Cellular, and Developmental Biology, and Genetics, Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026031907502038000_2026.03.13.711629v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2021.04.027"},{"key":"2026031907502038000_2026.03.13.711629v1.2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.51.10.3107"},{"key":"2026031907502038000_2026.03.13.711629v1.3","doi-asserted-by":"crossref","unstructured":"Alarcon-Martinez L , Shiga Y , Villafranca-Baughman D , Belforte N , Quintero H , Dotigny F , et al. Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma. Proc Natl Acad Sci U S A. 2022;119(7).","DOI":"10.1073\/pnas.2110329119"},{"key":"2026031907502038000_2026.03.13.711629v1.4","doi-asserted-by":"crossref","first-page":"108771","DOI":"10.1016\/j.exer.2021.108771","article-title":"Aging of the human choriocapillaris: Evidence that early pericyte damage can trigger endothelial changes","volume":"212","year":"2021","journal-title":"Exp Eye Res"},{"key":"2026031907502038000_2026.03.13.711629v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2023.06.001"},{"key":"2026031907502038000_2026.03.13.711629v1.6","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdf418"},{"key":"2026031907502038000_2026.03.13.711629v1.7","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X211056395"},{"issue":"3","key":"2026031907502038000_2026.03.13.711629v1.8","first-page":"e90905","article-title":"Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown","volume":"2","year":"2017","journal-title":"JCI Insight"},{"key":"2026031907502038000_2026.03.13.711629v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15296"},{"key":"2026031907502038000_2026.03.13.711629v1.10","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-061121-040127"},{"key":"2026031907502038000_2026.03.13.711629v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4288"},{"key":"2026031907502038000_2026.03.13.711629v1.12","doi-asserted-by":"publisher","DOI":"10.1101\/gad.398207"},{"key":"2026031907502038000_2026.03.13.711629v1.13","doi-asserted-by":"publisher","DOI":"10.1101\/gad.266803"},{"issue":"8","key":"2026031907502038000_2026.03.13.711629v1.14","doi-asserted-by":"crossref","first-page":"e42488","DOI":"10.1371\/journal.pone.0042488","article-title":"Platelet-derived growth factor over-expression in retinal progenitors results in abnormal retinal vessel formation","volume":"7","year":"2012","journal-title":"PLoS One"},{"key":"2026031907502038000_2026.03.13.711629v1.15","doi-asserted-by":"crossref","unstructured":"Diaz-Coranguez M , Ramos C , and Antonetti DA . The inner blood-retinal barrier: Cellular basis and development. Vision Res. 2017.","DOI":"10.1016\/j.visres.2017.05.009"},{"key":"2026031907502038000_2026.03.13.711629v1.16","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.118.311689"},{"key":"2026031907502038000_2026.03.13.711629v1.17","doi-asserted-by":"crossref","unstructured":"Zhang L , Levey J , Abedin M , Jo HN , Odame E , Howe M , et al. C1q limits cystoid edema by maintaining basal beta-catenin-dependent signaling and blood-retina barrier function. JCI Insight. 2025.","DOI":"10.1101\/2025.07.22.666172"},{"key":"2026031907502038000_2026.03.13.711629v1.18","doi-asserted-by":"crossref","unstructured":"Yemanyi F , Bora K , Blomfield AK , Wang Z , and Chen J . Wnt Signaling in Inner Blood-Retinal Barrier Maintenance. Int J Mol Sci. 2021;22(21).","DOI":"10.3390\/ijms222111877"},{"key":"2026031907502038000_2026.03.13.711629v1.19","doi-asserted-by":"crossref","unstructured":"Wang YC, C. ; Williams, J. ; Zhang, C. ; Junge, HJ. ; Nathans, J. Interplay of the Norrin and Wnt7a\/Wnt7b signaling systems in blood-brain barrier and blood-retina barrier development and maintenance. PNAS In press PMC Journal \u2013 In Process. 2018.","DOI":"10.1073\/pnas.1813217115"},{"key":"2026031907502038000_2026.03.13.711629v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(04)00216-8"},{"key":"2026031907502038000_2026.03.13.711629v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.10.042"},{"key":"2026031907502038000_2026.03.13.711629v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.07.048"},{"issue":"13","key":"2026031907502038000_2026.03.13.711629v1.23","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1016\/j.celrep.2017.06.004","article-title":"TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling","volume":"19","year":"2017","journal-title":"Cell Rep"},{"key":"2026031907502038000_2026.03.13.711629v1.24","doi-asserted-by":"crossref","unstructured":"Bruguera ES , Mahoney JP , and Weis WI. The co-receptor Tspan12 directly captures Norrin to promote ligand-specific beta-catenin signaling. bioRxiv. 2024.","DOI":"10.7554\/eLife.96743.1"},{"issue":"8","key":"2026031907502038000_2026.03.13.711629v1.25","doi-asserted-by":"crossref","first-page":"107415","DOI":"10.1016\/j.isci.2023.107415","article-title":"A Frizzled4-LRP5 agonist promotes blood-retina barrier function by inducing a Norrin-like transcriptional response","volume":"26","year":"2023","journal-title":"iScience"},{"key":"2026031907502038000_2026.03.13.711629v1.26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1821122116"},{"key":"2026031907502038000_2026.03.13.711629v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-24476-y"},{"key":"2026031907502038000_2026.03.13.711629v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.07.047"},{"key":"2026031907502038000_2026.03.13.711629v1.29","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202113977"},{"key":"2026031907502038000_2026.03.13.711629v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37689-1"},{"issue":"6","key":"2026031907502038000_2026.03.13.711629v1.31","doi-asserted-by":"crossref","first-page":"109938","DOI":"10.1016\/j.isci.2024.109938","article-title":"Design principles and therapeutic applications of novel synthetic WNT signaling agonists","volume":"27","year":"2024","journal-title":"iScience"},{"key":"2026031907502038000_2026.03.13.711629v1.32","doi-asserted-by":"crossref","unstructured":"Nguyen H , Lee SJ , and Li Y . Selective Activation of the Wnt-Signaling Pathway as a Novel Therapy for the Treatment of Diabetic Retinopathy and Other Retinal Vascular Diseases. Pharmaceutics. 2022;14(11).","DOI":"10.3390\/pharmaceutics14112476"},{"key":"2026031907502038000_2026.03.13.711629v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2023.03.008"},{"key":"2026031907502038000_2026.03.13.711629v1.34","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.tice.2018.03.010","article-title":"Spatial and temporal recruitment of the neurovascular unit during development of the mouse blood-retinal barrier","volume":"52","year":"2018","journal-title":"Tissue Cell"},{"key":"2026031907502038000_2026.03.13.711629v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/nature09002"},{"key":"2026031907502038000_2026.03.13.711629v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01738-3"},{"key":"2026031907502038000_2026.03.13.711629v1.37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0152833"},{"key":"2026031907502038000_2026.03.13.711629v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2023.11.023"},{"issue":"894","key":"2026031907502038000_2026.03.13.711629v1.39","doi-asserted-by":"crossref","first-page":"eadt0983","DOI":"10.1126\/scisignal.adt0983","article-title":"The MDM2-p53 axis regulates norrin\/frizzled4 signaling and blood-CNS barrier function","volume":"18","year":"2025","journal-title":"Sci Signal"},{"key":"2026031907502038000_2026.03.13.711629v1.40","doi-asserted-by":"publisher","DOI":"10.1242\/dev.126.14.3047"},{"issue":"1","key":"2026031907502038000_2026.03.13.711629v1.41","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/s42003-022-03180-8","article-title":"Characterisation of PDGF-BB:PDGFRbeta signalling pathways in human brain pericytes: evidence of disruption in Alzheimer\u2019s disease","volume":"5","year":"2022","journal-title":"Commun Biol"},{"key":"2026031907502038000_2026.03.13.711629v1.42","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-1909"},{"key":"2026031907502038000_2026.03.13.711629v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2017.10.006"},{"key":"2026031907502038000_2026.03.13.711629v1.44","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16330"},{"key":"2026031907502038000_2026.03.13.711629v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.pathophys.2017.07.001"},{"key":"2026031907502038000_2026.03.13.711629v1.46","doi-asserted-by":"crossref","unstructured":"Wong TY , Cheung CM , Larsen M , Sharma S , and Simo R . Diabetic retinopathy. Nat Rev Dis Primers. 2016;2:16012.","DOI":"10.1038\/nrdp.2016.12"},{"key":"2026031907502038000_2026.03.13.711629v1.47","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-023-09900-w"},{"key":"2026031907502038000_2026.03.13.711629v1.48","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.317473"},{"key":"2026031907502038000_2026.03.13.711629v1.49","unstructured":"Wykoff CS, M . AMARONE Shows Promising Outcomes for a Novel Treatment Pathway in DME and nAMD. Retinal Physician. 2024;21(April)."},{"issue":"9","key":"2026031907502038000_2026.03.13.711629v1.50","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1167\/tvst.11.9.19","article-title":"SZN-413, a FZD4 Agonist, as a Potential Novel Therapeutic for the Treatment of Diabetic Retinopathy","volume":"11","year":"2022","journal-title":"Transl Vis Sci Technol"},{"key":"2026031907502038000_2026.03.13.711629v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2017.11.008"},{"key":"2026031907502038000_2026.03.13.711629v1.52","doi-asserted-by":"crossref","unstructured":"Liu Y , Noda K , Murata M , Wu D , Kanda A , and Ishida S . Blockade of Platelet-Derived Growth Factor Signaling Inhibits Choroidal Neovascularization and Subretinal Fibrosis in Mice. J Clin Med. 2020;9(7).","DOI":"10.3390\/jcm9072242"},{"key":"2026031907502038000_2026.03.13.711629v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2723"},{"key":"2026031907502038000_2026.03.13.711629v1.54","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0143407"},{"key":"2026031907502038000_2026.03.13.711629v1.55","doi-asserted-by":"crossref","unstructured":"Wang J , Fang CL , Noller K , Wei Z , Liu G , Shen K , et al. Bone-derived PDGF-BB drives brain vascular calcification in male mice. J Clin Invest. 2023;133(23).","DOI":"10.1172\/JCI168447"},{"key":"2026031907502038000_2026.03.13.711629v1.56","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111580"},{"key":"2026031907502038000_2026.03.13.711629v1.57","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00476"},{"key":"2026031907502038000_2026.03.13.711629v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4309"},{"key":"2026031907502038000_2026.03.13.711629v1.59","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05367-2"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.13.711629","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T14:50:34Z","timestamp":1773931834000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.13.711629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,17]]},"references-count":59,"URL":"https:\/\/doi.org\/10.64898\/2026.03.13.711629","relation":{},"subject":[],"published":{"date-parts":[[2026,3,17]]},"subtype":"preprint"}}