{"doi":"10.1016/j.ymthe.2020.06.014","title":"VEGF-B Gene Therapy for the Heart: Proceed with Caution","abstract":"An unfortunate circumstance in biology is that the vascular endothelial growth factor type B (VEGF-B) was identified only after its homolog family member VEGF-A had already been discovered.1Olofsson B. Pajusola K. Kaipainen A. von Euler G. Joukov V. Saksela O. Orpana A. Pettersson R.F. Alitalo K. Eriksson U. Vascular endothelial growth factor B, a novel growth factor for endothelial cells.Proc. Natl. Acad. Sci. USA. 1996; 93: 2576-2581Crossref PubMed Scopus (622) Google Scholar Should the opposite have occurred, VEGF-B would likely not have been named as such. Indeed, VEGF-B is a poor growth factor for endothelial cells and, unlike VEGF-A, it is not angiogenic in the strict sense, while its only known main receptor, VEGFR-1, is expressed in endothelial cells as well as in a vast series of other cell types. Little was known about the non-angiogenic functions of selective VEGFR-1 ligands until a study in 2008 showed marked anti-apoptotic effects of VEGF-B, both in vitro and in vivo.2Li Y. Zhang F. Nagai N. Tang Z. Zhang S. Scotney P. Lennartsson J. Zhu C. Qu Y. Fang C. et al.VEGF-B inhibits apoptosis via VEGFR-1-mediated suppression of the expression of BH3-only protein genes in mice and rats.J. Clin. Invest. 2008; 118: 913-923Crossref PubMed Scopus (8) Google Scholar Subsequent studies confirmed cell-protective functions of this factor in different cell types. In this issue of Molecular Therapy, Lähteenvuo et al.3Lähteenvuo J. Hätinen O.P. Kuivanen A. Huusko J. Paananen J. Lähteenvuo M. Nurro J. Hedman M. Hartikainen J. Laham-Karam N. et al.Susceptibility to Cardiac Arrhythmias and Sympathetic Nerve Growth in VEGF-B Overexpressing Myocardium.Mol. Ther. 2020; 28 (this issue): 1731-1740Abstract Full Text Full Text PDF Scopus (11) Google Scholar add a new piece to the puzzle of VEGF-B activities. By using an adenoviral vector to overexpress VEGF-B186, they show that this factor induces sympathetic nerve sprouting in mouse and pig hearts via a VEGFR-1 signaling-independent mechanism. The integrity of cardiac innervation is very important for electrical stability, contractility, myocardial metabolism, and coronary function.4Jamali H.K. Waqar F. Gerson M.C. Cardiac autonomic innervation.J. Nucl. Cardiol. 2017; 24: 1558-1570Crossref PubMed Scopus (22) Google Scholar Therefore, the induction of cardiac re-innervation by the VEGF-B186 transgene should theoretically enhance post-ischemia cardiac recovery. Nonetheless, the authors report an association between a likely disordered nerve sprouting5Fukuda K. Kanazawa H. Aizawa Y. Ardell J.L. Shivkumar K. Cardiac innervation and sudden cardiac death.Circ. Res. 2015; 116: 2005-2019Crossref PubMed Scopus (211) Google Scholar and increased risk of ventricular arrhythmias and sudden cardiac death in pigs, at 6 days after infarction, unlike any other VEGFs tested in their previous studies. The authors should be commended for their rigorous approach based on retrospective analysis of 334 pigs and statistics, more usually utilized in the clinical studies realm. Such careful evaluation revealed an intrinsic risk in cardiac VEGF-B186 gene therapy, whereas pre-clinical studies, strictly prospective and necessarily based on smaller sample sizes, usually tend to overemphasize beneficial effects of experimental therapies, paying little attention to untoward events. Does the observation by Lähteenvuo et al.3Lähteenvuo J. Hätinen O.P. Kuivanen A. Huusko J. Paananen J. Lähteenvuo M. Nurro J. Hedman M. Hartikainen J. Laham-Karam N. et al.Susceptibility to Cardiac Arrhythmias and Sympathetic Nerve Growth in VEGF-B Overexpressing Myocardium.Mol. Ther. 2020; 28 (this issue): 1731-1740Abstract Full Text Full Text PDF Scopus (11) Google Scholar raise a red flag on the therapeutic utilization of VEGF-B gene transfer in the heart? Not necessarily. If the goal is angiogenesis, VEGF-A or VEGF-D are more established therapeutic factors. Despite the fact that VEGF-A binds with 10-fold greater affinity to VEGFR-1 than to","journal":"Molecular Therapy","year":2020,"id":108988,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9679,"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":520976,"name":"Fabio A. Recchia","orcid":"0000-0002-4189-8465","position":1,"is_corresponding":false},{"id":520975,"name":"Mauro Giacca","orcid":"0000-0003-2927-7225","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-18T23:12:46.854423Z","pmid":"32574553","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":[]}