{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T14:00:42Z","timestamp":1781704842148,"version":"3.54.5"},"reference-count":79,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T00:00:00Z","timestamp":1643068800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK116648"],"award-info":[{"award-number":["R01 DK116648"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01 DK129260"],"award-info":[{"award-number":["R01 DK129260"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The study investigated the cellular and molecular mechanisms in the peripheral nervous system (PNS) underlying the symptoms of urologic chronic pelvic pain syndrome (UCPPS) in mice. This work also aimed to test the feasibility of reversing peripheral sensitization <jats:italic>in vivo<\/jats:italic> in alleviating UCPPS symptoms. Intravesical instillation of vascular endothelial growth factor A (VEGF<jats:sub>A<\/jats:sub>) was used to induce UCPPS-like symptoms in mice. Spontaneous voiding spot assays and manual Von Frey tests were used to evaluate the severity of lower urinary tract symptoms (LUTS) and visceral hypersensitivity in VEGF<jats:sub>A<\/jats:sub>-instilled mice. Bladder smooth muscle strip contractility recordings (BSMSC) were used to identify the potential changes in myogenic and neurogenic detrusor muscle contractility at the tissue-level. Quantitative real-time PCR (qPCR) and fluorescent immunohistochemistry were performed to compare the expression levels of VEGF receptors and nociceptors in lumbosacral dorsal root ganglia (DRG) between VEGF<jats:sub>A<\/jats:sub>-instilled mice and saline-instilled controls. To manipulate primary afferent activity, Gi-coupled <jats:underline><jats:italic>D<\/jats:italic><\/jats:underline>esigner <jats:underline><jats:italic>R<\/jats:italic><\/jats:underline>eceptors <jats:underline><jats:italic>E<\/jats:italic><\/jats:underline>xclusively <jats:underline><jats:italic>A<\/jats:italic><\/jats:underline>ctivated by <jats:underline><jats:italic>D<\/jats:italic><\/jats:underline>esigner <jats:underline><jats:italic>D<\/jats:italic><\/jats:underline>rugs (Gi-DREADD) were expressed in lumbosacral DRG neurons of <jats:italic>TRPV1-Cre-ZGreen<\/jats:italic> mice via targeted adeno-associated viral vector (AAVs) injections. A small molecule agonist of Gi-DREADD, clozapine-N-oxide (CNO), was injected into the peritoneum (<jats:italic>i<\/jats:italic>. <jats:italic>p<\/jats:italic>.) in awake animals to silence TRPV1 expressing sensory neurons <jats:italic>in vivo<\/jats:italic> during physiological and behavioral recordings of bladder function. Intravesical instillation of VEGF<jats:sub>A<\/jats:sub> in the urinary bladders increased visceral mechanical sensitivity and enhanced RTX-sensitive detrusor contractility. Sex differences were identified in the baseline detrusor contractility responses and VEGF-induced visceral hypersensitivity. VEGF<jats:sub>A<\/jats:sub> instillations in the urinary bladder led to significant increases in the mRNA and protein expression of transient receptor potential cation channel subfamily A member 1 (TRPA1) in lumbosacral DRG, whereas the expression levels of transient receptor potential cation channel subfamily V member 1 (TRPV1) and VEGF receptors (VEGFR1 and VEGFR2) remained unchanged when compared to saline-instilled animals. Importantly, the VEGF<jats:sub>A<\/jats:sub>-induced visceral hypersensitivity was reversed by Gi-DREADD-mediated neuronal silencing in lumbosacral sensory neurons. Activation of bladder VEGF signaling causes sensory neural plasticity and visceral hypersensitivity in mice, confirming its role of an UCPPS biomarker as identified by the <jats:underline><jats:italic>M<\/jats:italic><\/jats:underline>ultidisciplinary <jats:underline><jats:italic>A<\/jats:italic><\/jats:underline>pproach to the <jats:italic>S<\/jats:italic>tudy of <jats:italic>C<\/jats:italic>hronic <jats:underline><jats:italic>P<\/jats:italic><\/jats:underline>elvic <jats:underline><jats:italic>P<\/jats:italic><\/jats:underline>ain (MAPP) research studies. Pharmacogenetic inhibition of lumbosacral sensory neurons <jats:italic>in vivo<\/jats:italic> completely reversed VEGF<jats:sub>A<\/jats:sub>-induced pelvic hypersensitivity in mice, suggesting the strong therapeutic potential for decreasing primary afferent activity in the treatment of pain severity in UCPPS patients.<\/jats:p>","DOI":"10.1371\/journal.pone.0262769","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T18:36:15Z","timestamp":1643135775000},"page":"e0262769","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Pharmacogenetic inhibition of lumbosacral sensory neurons alleviates visceral hypersensitivity in a mouse model of chronic pelvic pain"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4395-8510","authenticated-orcid":true,"given":"Alison Xiaoqiao","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nao","family":"Iguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor C.","family":"Clarkson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9271-3096","authenticated-orcid":true,"given":"Anna P.","family":"Malykhina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,1,25]]},"reference":[{"key":"pone.0262769.ref001","article-title":"Urologic chronic pelvic pain syndrome: insights from the MAPP Research Network.","author":"JQ Clemens","journal-title":"Nat Rev Urol"},{"key":"pone.0262769.ref002","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.neuroscience.2007.07.053","article-title":"Neural mechanisms of 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