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Deletion of neuropilin 2 enhances detrusor contractility following bladder outlet obstruction
Evalynn Vasquez, … , Maryrose P. Sullivan, Rosalyn M. Adam
Evalynn Vasquez, … , Maryrose P. Sullivan, Rosalyn M. Adam
Published February 9, 2017
Citation Information: JCI Insight. 2017;2(3):e90617. https://doi.org/10.1172/jci.insight.90617.
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Research Article Muscle biology Therapeutics

Deletion of neuropilin 2 enhances detrusor contractility following bladder outlet obstruction

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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

Evalynn Vasquez, Vivian Cristofaro, Stefan Lukianov, Fiona C. Burkhard, Ali Hashemi Gheinani, Katia Monastyrskaya, Diane R. Bielenberg, Maryrose P. Sullivan, Rosalyn M. Adam

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Figure 1

Partial bladder outlet obstruction (pBOO) in wild-type mice reveals time-dependent compensation and decompensation phases.

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Partial bladder outlet obstruction (pBOO) in wild-type mice reveals time...
(A–D) Contractile responses of bladder muscle strips from wild-type male mice subjected to pBOO (dark gray boxes) for 1 to 2 weeks (n = 11), 4 weeks (n = 10), or sham operation (light gray box, n = 15) were determined by isometric tension testing in response to electrical field stimulation (A), carbachol (B), α,β-methyl-adenosine triphosphate (α,β-meATP) (C), and potassium chloride (KCl) (D). Line graphs in A and B show mean ± SEM; box-and-whisker plots in C and D show median (line within the box), upper and lower quartiles (bounds of the box), and 90th and 10th percentiles (whiskers). Contractile responses from obstructed mice were higher than sham at 1 to 2 weeks after obstruction, but trended to lower contractility at 4 weeks after obstruction. *P < 0.05, significantly greater than sham and 4-week pBOO; #P < 0.05, significantly greater than 4-week pBOO; &P < 0.05, significantly different than sham; ANOVA followed by Holm-Sidak multiple comparison test. mN, millinewtons.

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