Context: Infiltrating neutrophil granulocytes are a particularly rich source of vascular endothelial growth factor (VEGF) in the endometrium and may contribute to the angiogenesis of endometriosis lesions.

Objective: To evaluate the expression and regulation of VEGF in endometrial neutrophils and in a model of neutrophil differentiation relevant to endometriosis.

Design: Immunohistochemistry of endometriosis patient biopsies and assessment of cultured neutrophil-like HL-60 cells.

Setting: Reproductive biology division within an academic medical center.

Interventions: Endometrial biopsies of women with endometriosis; treatment of HL-60 cells with all-trans retinoic acid and dimethyl sulfoxide in vitro.

Main outcome measures: Immunofluorescence histochemistry; VEGF mRNA and protein quantification; transfection studies of VEGF gene promoter-luciferase constructs.

Results: Immunofluorescence studies verified the presence of neutrophils in eutopic endometrium from women with endometriosis. Examination of the regulation of VEGF using differentiated HL-60 cells as a model, revealed that all-trans retinoic acid (atRA) induced a dose- and time-dependent suppression of VEGF mRNA and protein. Transient transfection, truncation, electrophoretic mobility-shift assays and site-directed mutagenesis of human VEGF promoter-luciferase constructs in HL-60 cells indicated that atRA repressed VEGF gene transcription via a direct repeat (DR)-1 element located between -443 and -431 bp relative to the transcription initiation site.

Conclusions: As retinoic acid is synthesized de novo in endometrial cells under the influence of progesterone, our findings suggest that the upregulated VEGF and angiogenesis in tissue from women with endometriosis may reflect failure of neutrophil differentiation in these cases, and provide a rationale for retinoid therapy in this condition.