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Innervation of the degenerating intervertebral disc (IVD) is suspected to cause discogenic LBP, but the mechanisms that orchestrate the IVD\u2019s neo-innervation and subsequent symptoms of LBP remain unknown. We hypothesize that Vascular Endothelial Growth Factor-A (VEGFA) critically mediates the neurite invasion in the IVD and contributes to chronic LBP. Initiating IVD degeneration through a mechanical injury, we evaluated the progression of neurovascular features into the IVD, as well as ensuring LBP symptoms and locomotive impairments at acute (3-weeks) and chronic (12-weeks) timepoints following the IVD injury. To determine the role of VEGFA, we utilized a mouse model with ubiquitously inducible recombination of the floxed\n                  <jats:italic>Vegfa<\/jats:italic>\n                  allele (UBC-Cre\n                  <jats:sup>ERT2<\/jats:sup>\n                  ;\n                  <jats:italic>Vegfa<\/jats:italic>\n                  <jats:sup>fl\/fl<\/jats:sup>\n                  ). The ablation of VEGFA after an IVD injury attenuated\n                  <jats:italic>de novo<\/jats:italic>\n                  neurite and vessel infiltration and impeded the expression of TRPA1, a nociceptive ion channel, in the dorsal root ganglion. The VEGFA-null animals, despite IVD degeneration, exhibited alleviated mechanical allodynia and improved locomotive performance. To determine the effects of IVD-derived VEGFA on endothelial cells and neurons, we co-cultured HMEC-1 endothelial cells and SH-SY5Y neurons with\n                  <jats:italic>VEGFA<\/jats:italic>\n                  -silenced human primary IVD cells. The endothelial cells co-cultured with\n                  <jats:italic>VEGFA<\/jats:italic>\n                  -silenced IVD cells exhibited reduced vessel growth and shifted their transcriptome and secretome from angiogenic to lymphangiogenic. The neurons co-cultured\n                  <jats:italic>VEGFA<\/jats:italic>\n                  -silenced IVD cells showed slowed growth and attenuated transcriptional programs for growth and elongation. These results show that VEGFA directs the growth of intradiscal vessels and neurites that cause low back pain and impaired function, and the inhibition of IVD-derived VEGFA during degeneration may be sufficient to prevent chronic pain behavior and motor impairment associated with discogenic low back pain.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>VEGFA is a key mediator of neurovascular infiltration in the degenerating intervertebral disc and an essential driver of chronic low back pain, whose ablation prevents pain-related behaviors.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.06.03.657641","type":"posted-content","created":{"date-parts":[[2025,6,7]],"date-time":"2025-06-07T19:20:12Z","timestamp":1749324012000},"source":"Crossref","is-referenced-by-count":1,"title":["VEGFA critically controls neurovascular invasion and chronic low back pain during intervertebral disc degeneration"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3740-1288","authenticated-orcid":false,"given":"Ryan S.","family":"Potter","sequence":"first","affiliation":[{"name":"Department of Mechanical Engineering and Materials Science, Washington University in St. Louis"},{"name":"Department of Orthopaedic Surgery, Washington University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong J.","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Washington University School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9798-2594","authenticated-orcid":false,"given":"Sade W.","family":"Clayton","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Washington University School of 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