Neuropilin-VEGF signaling pathway acts as a key modulator of vascular, lymphatic, and inflammatory cell responses of the bladder to intravesical BCG treatment.

Abstract

Recent findings indicate that VEGF receptors and coreceptors (neuropilins; NRP) are expressed on nonendothelial cells in human bladder urothelium, in one human bladder cancer cell line (J82), and in the mouse bladder urothelium. In addition, VEGFR1, VEGFR2, NRP1, and NRP2 expressions were upregulated in animal models of chronic bladder inflammation induced by four weekly instillations of protease-activated receptors (PAR)-activating peptides or bacillus Calmette-Guérin (BCG) into the mouse bladder. Here, we used four weekly instillations of BCG as a model for chronic bladder inflammation to further investigate whether VEGF receptors and NRPs play a role in the migration of inflammatory cells and inflammation-induced lymphangiogenesis and angiogenesis. For this purpose, we used neutralizing antibodies that were engineered to specifically block the binding of VEGF to NRP (anti-NRP1(B)) and the binding of semaphorins to NRP (anti-NRP1(A)). C57BL/6 mice received intraperitoneal injections of PBS, anti-NRP1(A)- or anti-NRP1(B)-neutralizing antibodies and then were challenged chronically with intravesical PBS or BCG. At the end of chronic challenge period, a fluorescent internalizable tracer, scVEGF/Cy5.5, was administered to all mice and near-infrared fluorescence images were obtained in vivo and in real time. BCG increased the overall accumulation of scVEGF/Cy5.5 in the urinary bladder urothelium and inflammatory cells. In addition, BCG increased the density of blood and lymphatic vessels concomitantly with an upregulation of NRP2 expression in lymphatic vessels. Treatment of the mice with NRP1-neutralizing antibodies dramatically reduced scVEGF/Cy5.5 uptake, polymorphonuclear (myeloperoxidase-positive cells) and dendritic cell (CD11c-positive cells) infiltration, and decreased the overall density of BCG-induced blood and lymphatic vessels. These results implicate NRPs as critical in vivo regulators of the vascular and inflammatory responses to the intravesical administration of BCG.

• Authors: Marcia R Saban, Thomas J Sferra, Carole A Davis, Cindy Simpson, Arielle Allen, Julie Maier, Ben Fowler, Nicholas Knowlton, Lori Birder, Xue-Ru Wu, Ricardo Saban
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 299 Issue 6 Pg. F1245-56 (Dec 2010) ISSN: 1522-1466 [Electronic] United States
• PMID: 20861073 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• BCG Vaccine
• Neuropilins
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Neuropilin-1
• Receptors, Vascular Endothelial Growth Factor

Topics

• Animals
• BCG Vaccine
• Cell Movement (immunology)
• Cystitis (chemically induced, physiopathology)
• Female
• Humans
• Lymphangiogenesis (drug effects)
• Mice
• Mice, Inbred C57BL
• Neovascularization, Pathologic (physiopathology)
• Neuropilin-1 (immunology, physiology)
• Neuropilins (physiology)
• Receptors, Vascular Endothelial Growth Factor (physiology)
• Signal Transduction (physiology)
• Urinary Bladder (blood supply, metabolism)
• Vascular Endothelial Growth Factor A (biosynthesis)