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Vascular Endothelial Growth Factor Drives Autocrine Epithelial Cell Proliferation and Survival in Chronic Rhinosinusitis with Nasal Polyposis

¹ Department of Allergy and Clinical Immunology and ² Department of Otolaryngology, Head and Neck Surgery, Johns Hopkins Asthma and Allergy Center, Johns Hopkins Bayview Medical Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Jean Kim, M.D., Ph.D., Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Room 3B65A, Baltimore, MD 21224. E-mail: jeankim{at}jhmi.edu

Rationale: The pathogenesis of nasal polyps in chronic rhinosinusitis is poorly understood.

Objectives: 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.

Measurements and Main 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.

Key Words: chronic rhinosinusitis with nasal polyposis • vascular endothelial cell growth factor • epithelial cell growth • apoptosis • neuropilin-1

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Chronic rhinosinusitis with nasal polyposis is a disease characterized by recurrent and recalcitrant hyperplastic polyp growth, the pathogenesis of which is poorly understood. What This Study Adds to the Field These studies define a novel role for vascular endothelial growth factor as an autocrine epithelial cell mitogen and prosurvival factor that drives the epithelial cell hyperplasia observed in hyperplastic chronic rhinosinusitis with nasal polyposis.