Functional effects of blocking VEGF/VEGFR2 signaling in the rat urinary bladder in acute and chronic CYP-induced cystitis.

High expression of vascular endothelial growth factor (VEGF) is associated with immature angiogenesis within the urinary bladder wall and bladder afferent nerve sensitization leading to visceral hyperalgesia and pelvic pain. Research suggests a shift in VEGF alternative splice variant (VEGF-Axxxa, VEGF-Axxxb) expression with several pathologies (e.g., neuropathic pain and inflammation), as well as exhibiting differing effects on pain. Translational studies have also demonstrated increased total VEGF expression in the bladder of women with Interstitial cystitis/Bladder pain syndrome (IC/BPS). In this study, we quantified VEGF alternative splice variant expression in LUT tissues under control conditions and with CYP-induced cystitis. Using conscious cystometry, we further determined the functional effects of VEGFR2 receptor blockade on bladder function using intravesical instillation of a potent and selective VEGFR2 tyrosine kinase inhibitor (Ki8751, 1 mg/kg) in Wistar rats (male and female) with acute and chronic CYP-induced cystitis and controls (no CYP). With VEGFR2 receptor blockade, bladder capacity increased (p ≤ 0.01) in male and female control rats, as well as male and female rats with acute (p ≤ 0.05) or chronic (p ≤ 0.01, p ≤ 0.05 respectively) CYP-induced cystitis. Void volume also increased in female control (p ≤ 0.01) rats and female rats with acute (p ≤ 0.05) or chronic (p ≤ 0.05) CYP-induced cystitis, as well as in male control (p ≤ 0.05) rats and male rats with chronic (p ≤ 0.01) CYP-induced cystitis. These data suggest that VEGF may be a biomarker for IC/BPS and targeting VEGF/VEGFR2 signaling may be an effective treatment.

American journal of physiology. Renal physiology. 2019 Apr 17 [Epub ahead of print]

Katharine Tooke, Beatrice M Girard, Margaret A Vizzard

Neurological Sciences, The University of Vermont, United States., Department of Anatomy and Neurobiology, University of Vermont., Neurological Sciences, University of Vermont, United States.

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