Vascular endothelial growth factor drives autocrine epithelial cell proliferation and survival in chronic rhinosinusitis with nasal polyposis.
BACKGROUND
The pathogenesis of nasal polyps in chronic rhinosinusitis is poorly understood.


OBJECTIVE
These studies seek to implicate a functional role for vascular endothelial growth factor (VEGF) in perpetuating primary nasal epithelial cell overgrowth, a key feature of hyperplastic polyps.


METHODS
Comparison of VEGF and receptor expression was assessed by ELISA of nasal lavage, immunohistochemistry of sinus tissue, flow cytometry of nasal epithelial cells, and ELISA of supernatants. VEGF-dependent cell growth and apoptosis were assessed with blocking antibodies to VEGF, their receptors, or small interfering RNA knockdown of neuropilin-1 by cell proliferation assays and flow cytometric binding of annexin V.


RESULTS
VEGF protein was sevenfold higher in nasal lavage from patients with polyposis compared with control subjects (P < 0.001). We also report elevated expression of VEGF (P < 0.012), receptors VEGFR2 and phospho-VEGFR2 (both P < 0.04), and identification of VEGF coreceptor neuropilin-1 in these tissues. Nasal epithelial cells from patients with polyps demonstrated faster growth rates (P < 0.005). Exposure of cells to blocking antibodies against VEGF resulted in inhibition of cell growth (P < 0.05). VEGF receptor blockade required blockade of neuropilin-1 (P < 0.05) and resulted in increased apoptosis (P < 0.001) and inhibition of autocrine epithelial VEGF production (P < 0.05).


CONCLUSIONS
These data demonstrate that VEGF is a novel biomarker for chronic rhinosinusitis with hyperplastic sinonasal polyposis that functions in an autocrine feed-forward manner to promote nasal epithelial cell growth and to inhibit apoptosis. These findings implicate a previously unrecognized and novel role of VEGF functioning through neuropilin-1 on nonneoplastic primary human airway epithelial cells, to amplify cell growth, contributing to exuberant hyperplastic polyposis.
Lee
Hyun Sil
HS
Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Room 3B65A, Baltimore, MD 21224, USA.
Myers
Allen
A
Kim
Jean
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002470:Cell Survival; D002908:Chronic Disease; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D009296:Nasal Cavity / Q000378:metabolism* / Q000648:ultrastructure; D017817:Nasal Lavage Fluid; D009298:Nasal Polyps / Q000378:metabolism; D012220:Rhinitis / Q000378:metabolism*; D012852:Sinusitis / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D055815:Young Adult
D015415:Biomarkers; D042461:Vascular Endothelial Growth Factor A