title: Deletion of neuropilin 2 enhances detrusor contractility following bladder outlet obstruction.
abstract: Chronic urethral obstruction and the ensuing bladder wall remodeling can lead to diminished bladder smooth muscle (BSM) contractility and debilitating lower urinary tract symptoms. No effective pharmacotherapy exists to restore BSM contractile function. Neuropilin 2 (Nrp2) is a transmembrane protein that is highly expressed in BSM. Nrp2 deletion in mice leads to increased BSM contraction. We determined whether genetic ablation of Nrp2 could restore BSM contractility following obstruction. Partial bladder outlet obstruction (pBOO) was created by urethral occlusion in mice with either constitutive and ubiquitous, or inducible smooth muscle-specific deletion of Nrp2, and Nrp2-intact littermates. Mice without obstruction served as additional controls. Contractility was measured by isometric tension testing. Nrp2 deletion prior to pBOO increased force generation in BSM 4 weeks following surgery. Deletion of Nrp2 in mice already subjected to pBOO for 4 weeks showed increased contractility of tissues tested 6 weeks after surgery compared with nondeleted controls. Assessment of tissues from patients with urodynamically defined bladder outlet obstruction revealed reduced NRP2 levels in obstructed bladders with compensated compared with decompensated function, relative to asymptomatic controls. We conclude that downregulation of Nrp2 promotes BSM force generation. Neuropilin 2 may represent a novel target to restore contractility following obstruction.
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital.|Department of Surgery, Harvard Medical School.
authors.forename: Evalynn
authors.initials: E
authors.lastname: Vasquez
authors.affiliation: Department of Surgery, Harvard Medical School.|Division of Urology, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Cristofaro
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lukianov
authors.affiliation: Urology Research Laboratory, Department of Clinical Research, Universität Bern, Bern, Switzerland.
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Burkhard
authors.affiliation: Urology Research Laboratory, Department of Clinical Research, Universität Bern, Bern, Switzerland.
authors.forename: Ali Hashemi
authors.initials: AH
authors.lastname: Gheinani
authors.affiliation: Urology Research Laboratory, Department of Clinical Research, Universität Bern, Bern, Switzerland.
authors.forename: Katia
authors.initials: K
authors.lastname: Monastyrskaya
authors.affiliation: Department of Surgery, Harvard Medical School.|Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Diane R
authors.initials: DR
authors.lastname: Bielenberg
authors.affiliation: Department of Surgery, Harvard Medical School.|Division of Urology, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA.
authors.forename: Maryrose P
authors.initials: MP
authors.lastname: Sullivan
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital.|Department of Surgery, Harvard Medical School.
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Adam
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques / Q000379:methods*; D006801:Humans; D007537:Isometric Contraction; D008297:Male; D051379:Mice; D039943:Neuropilin-2 / Q000235:genetics*; D001743:Urinary Bladder / Q000502:physiology*; D001748:Urinary Bladder Neck Obstruction / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D014563:Urodynamics
chemical_list: D039943:Neuropilin-2; C581308:neuropilin-2, human