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1 Physiology, OUHSC, Oklahoma City, Oklahoma, United States
2 SibTech, Inc, Newington, Connecticut, United States
3 mbacker@sibtech.com, Newington, Connecticut, United States
4 Imaging Core Facility, Oklahoma Medical Research Foundation (OMRF),, Oklahoma City, Oklahoma, United States
5 Imaging Core Facility,, 3Oklahoma Medical Research Foundation (OMRF),, Oklahoma City, Oklahoma, United States
6 Urology, New York University, Medical School, New York, New York, United States
7 Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
8 Children's Hospital, Harvard Med School, United States
9 Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
10 Urology, Biochemistry, and Molecular Biology, OUHSC, Oklahoma City, Oklahoma, United States
* To whom correspondence should be addressed. E-mail: ricardo-saban{at}ouhsc.edu.
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 co-localization 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 co-receptors 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 up-regulation 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.
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  B. P. Cheppudira, B. M. Girard, S. E. Malley, K. C. Schutz, V. May, and M. A. Vizzard Upregulation of vascular endothelial growth factor isoform VEGF-164 and receptors (VEGFR-2, Npn-1, and Npn-2) in rats with cyclophosphamide-induced cystitis Am J Physiol Renal Physiol, September 1, 2008; 295(3): F826 - F836. [Abstract] [Full Text] [PDF]
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