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Notably, the lymphatic vasculature is responsive to CGRP signaling, but whether meningeal lymphatic vessels (MLVs) contribute to migraine pathophysiology is unknown. Mice with lymphatic vasculature deficient in the CGRP receptor (\n                    <jats:italic>\n                      Calcrl\n                      <jats:sup>iLEC<\/jats:sup>\n                    <\/jats:italic>\n                    mice) treated with nitroglycerin-mediated (NTG-mediated) chronic migraine exhibit reduced pain and light avoidance compared with NTG-treated littermate controls. Gene expression profiles of lymphatic endothelial cells (LECs) isolated from the meninges of\n                    <jats:italic>\n                      Rpl22\n                      <jats:sup>HA\/+<\/jats:sup>\n                      ;Lyve1\n                      <jats:sup>Cre<\/jats:sup>\n                    <\/jats:italic>\n                    RiboTag mice treated with NTG revealed increased MLV-immune interactions compared with cells from untreated mice. Interestingly, the relative abundance of mucosal vascular addressin cell adhesion molecule 1\u2013interacting (MAdCAM1-interacting) CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells was increased in the deep cervical lymph nodes of NTG-treated control mice but not in NTG-treated\n                    <jats:italic>\n                      Calcrl\n                      <jats:sup>iLEC<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Treatment of cultured hLECs with CGRP peptide in vitro induced vascular endothelial\u2013cadherin (VE-cadherin) rearrangement and reduced functional permeability. Likewise, intra cisterna magna injection of CGRP caused rearrangement of VE-cadherin, decreased MLV uptake of cerebrospinal fluid (CSF), and impaired CSF drainage in control mice but not in\n                    <jats:italic>\n                      Calcrl\n                      <jats:sup>iLEC<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Collectively, these findings reveal a previously unrecognized role for lymphatics in chronic migraine, whereby CGRP signaling primes MLV-immune interactions and reduces CSF efflux.\n                  <\/jats:p>","DOI":"10.1172\/jci175616","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T14:05:16Z","timestamp":1722434716000},"source":"Crossref","is-referenced-by-count":55,"title":["Meningeal lymphatic CGRP signaling governs pain via cerebrospinal fluid efflux and neuroinflammation in migraine models"],"prefix":"10.1172","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9388-2801","authenticated-orcid":true,"given":"Nathan P.","family":"Nelson-Maney","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"B\u00e1lint","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L.S.","family":"Beeson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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