{"doi":"10.17615/9k58-wt92","title":"The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching","abstract":"Blood vessel formation requires the integrated regulation of endothelial cell proliferation and branching morphogenesis, but how this coordinated regulation is achieved is not well understood. Flt-1 (vascular endothelial growth factor [VEGF] receptor 1) is a high affinity VEGF-A receptor whose loss leads to vessel overgrowth and dysmorphogenesis. We examined the ability of Flt-1 isoform transgenes to rescue the vascular development of embryonic stem cell–derived flt-1−/− mutant vessels. Endothelial proliferation was equivalently rescued by both soluble (sFlt-1) and membrane-tethered (mFlt-1) isoforms, but only sFlt-1 rescued vessel branching. Flk-1 Tyr-1173 phosphorylation was increased in flt-1−/− mutant vessels and partially rescued by the Flt-1 isoform transgenes. sFlt-1–rescued vessels exhibited more heterogeneous levels of pFlk than did mFlt-1–rescued vessels, and reporter gene expression from the flt-1 locus was also heterogeneous in developing vessels. Our data support a model whereby sFlt-1 protein is more efficient than mFlt-1 at amplifying initial expression differences, and these amplified differences set up local discontinuities in VEGF-A ligand availability that are important for proper vessel branching.","journal":"Carolina Digital Repository (University of North Carolina at Chapel Hill)","year":2020,"id":141396,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":607429,"name":"Surovi Hazarika","orcid":null,"position":1,"is_corresponding":false},{"id":32892,"name":"Brian H. Annex","orcid":"0000-0001-6538-8243","position":2,"is_corresponding":false},{"id":423152,"name":"Cam Patterson","orcid":null,"position":3,"is_corresponding":false},{"id":601243,"name":"Joseph B. Kearney","orcid":null,"position":4,"is_corresponding":false},{"id":302893,"name":"John C. Chappell","orcid":"0000-0002-0427-5170","position":5,"is_corresponding":false},{"id":500517,"name":"Victoria L. Bautch","orcid":"0000-0003-2135-5153","position":6,"is_corresponding":false},{"id":607430,"name":"Nicholas C. Kappas","orcid":null,"position":7,"is_corresponding":false},{"id":607431,"name":"Kimberly G. Kallianos","orcid":null,"position":8,"is_corresponding":false},{"id":607428,"name":"Gefei Zeng","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:24.429854Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}