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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/F60    most recent 00618.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Saban, M. R. Articles by Saban, R. PubMed PubMed Citation Articles by Saban, M. R. Articles by Saban, R.

VEGF receptors and neuropilins are expressed in the urothelial and neuronal cells in normal mouse urinary bladder and are upregulated in inflammation

¹Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City; ²SibTech, Incorporated, Brookfield, Connecticut; ³Oklahoma Medical Research Foundation, Imaging Core Facility, Oklahoma City; ⁴Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; ⁵Department of Urology, New York University Medical School, New York, New York; ⁶Departments of Urology, Surgery, and Biological Chemistry and Molecular Pharmacology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts; ⁷Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina; and ⁸Departments of Urology, Biochemistry, and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Submitted 28 December 2007 ; accepted in final form 1 May 2008

Recent evidence supports a role for vascular endothelium growth factor (VEGF) signaling in bladder inflammation. However, it is not clear what bladder cells are targeted by VEGF. Therefore, we determined the nature of cells responding to VEGF in normal and inflamed bladders by tagging such cells in vivo with a targeted fluorescent tracer, scVEGF/Cy, an engineered single-chain VEGF labeled with Cy5.5 dye, which identifies cells with accessible and functionally active VEGF receptors. Inflammation was induced by intravesical instillation of PAR-activating peptides or BCG. In vivo NIRF imaging with intravenously injected scVEGF/Cy revealed accumulation of the tracer in the control mouse bladder and established that inflammation increased the steady-state levels of tracer uptake. Ex vivo colocalization of Cy5.5 dye revealed that in normal and at a higher level in inflamed bladder, accumulation of scVEGF/Cy occurs in both urothelial and ganglial cells, expressing VEGF receptors VEGFR-1 and VEGFR-2, as well as VEGF coreceptors neuropilins (NRP) NRP1 and NRP2. PCR results indicate that the messages for VEGF-Rs and NRPs are present in the bladder mucosa and ChIP/QPCR analysis indicated that inflammation induced upregulation of genes encoding VEGFRs and NRPs. Our results strongly suggest new and blossoming VEGF-driven processes in bladder urothelial cells and ganglia in the course of inflammation. We expect that molecular imaging of the VEGF pathway in the urinary tract by receptor-mediated cell tagging in vivo will be useful for clinical diagnosis and therapeutic monitoring, and will help to accelerate the development of bladder-targeting drugs and treatments.

bladder inflammation; VEGF coreceptors; interstitial cystitis; VEGF receptor imaging; human urothelium; targeted imaging; scVEGF/Cy fluorescent tracer; Cy5.5

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