High-risk human papillomavirus-induced expression of endothelial and inducible nitric oxide synthase in human uterine cervix

Abstract

Introduction. Levels of nitric oxide metabolites are elevated in the cervical fluid of women with high-risk human papillomavirus (hrHPV). To elucidate the origin of this elevation we studied the cervical expression and localization of endothelial and inducible nitric oxide synthases (eNOS, iNOS) in women. Material and methods. Expression of eNOS and iNOS was studied by Western blotting in the uterine cervixes of 86 women with (n = 41) and without (n = 45) hrHPV infection. The localization of eNOS and iNOS in cervical cells was studied by immunohistochemistry in 32 randomly selected women. Results. Expression of eNOS and iNOS (in mean [95% CI] density units relative to actin) was higher in women with hrHPV versus those without (eNOS: 33.8 [22.5–45.1] versus 20.2 [6.1–34.3], P = 0.007; iNOS: 12.0 [7.1–16.9]) versus 5.6 [2.0–9.2], P = 0.003). Smoking reduced 64% eNOS (P = 0.001) and 68% iNOS (P = 0.008) in women with hrHPV. Endothelial NOS was localized in the vascular endothelium, while iNOS was present in basal squamous epithelial cells. Low-grade histological lesions were accompanied by elevated expression of both eNOS and iNOS. Conclusions. High-risk HPV-associated elevation in cervical fluid nitric oxide metabolites results from both eNOS and iNOS stimulation. However, smoking seems to suppress this stimulation in hrHPV-infected women.

Key words::

• Immunohistochemistry
• papillomavirus
• uterine cervix
• Western blot

Declaration of interest: This work was supported by the Clinical Research Fund of Helsinki University Central Hospital (grant number TYH2008261), National Graduate School of Clinical Investigation, the Research Foundation of Instrumentarium Corporation, the Research Foundation of Orion Corporation, the Finnish Cultural Foundation, the Finnish Medical Foundation, the Finnish Society against Sexually Transmitted Diseases, the Finnish-Norwegian Medical Research Foundation, the Maud Kuistila Memorial Foundation, the Finnish Gynaecological Society, and the Society of Gynaecological Surgery in Finland.

The authors declare that there are no conflicts of interest. Päivi Rahkola-Soisalo and Hanna Savolainen-Peltonen contributed equally.