Pathogenetic roles of angiogenic factors in pyogenic granulomas in pregnancy are modulated by female sex hormones

Background: An abundance of microvessels is the major phenotype of pyogenic granuloma, which has been considered a hormone-related lesion based on clinical observations. Although angiogenic factors and inflammatory cytokines have been implied to play roles in the pathogenesis of pyogenic granuloma, their links to female steroid hormones still remain to be elucidated. Since apoptosis is important in limiting inflammation, we also investigated whether steroid hormones could protect granuloma cells from apoptosis and, therefore, lead to over-reactive inflammatory response. Methods: We employed immunoassays in a series of experiments, including human pyogenic granuloma in pregnancy, mouse air pouch granuloma and U937 (monoblastoid) cells in culture to clarify the relationship among vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 beta and female steroid hormones in granuloma formation. The apoptotic rates were analyzed in vivo and in vitro by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick end labeling (TUNEL) and flow cytometry, respectively. Results: Both in human and animal studies, the immunoassays (enzyme-linked immunoabsorbent assay [ELISA] and immunohistochemistry) detected significantly more VEGF and bFGF and less TNF-α in hormones than the control group, while TUNEL assay revealed less apoptotic cells in groups with pregnancy levels of hormones. In vitro, progesterone enhanced the expression of VEGF in LPS-treated U937 cells. Both estrogen and progesterone inhibited the apoptosis of U937 cells triggered by exogenous TNF-α Conclusions: Female steroid hormones may have dual effects on the pathogenesis of pyogenic granuloma in pregnancy. The hormones not only enhance the expression of angiogenic factors in inflamed tissue, but also decrease apoptosis of granuloma cells to extend angiogenic effect.