Expression of vascular endothelial growth factor receptors in the human endometrium: Modulation during the menstrual cycle

Angiogenesis is fundamental for human endometrial development and different iation necessary for implantation. These vascular changes are thought to be mediated by the vascular endothelial growth factor (VEGF), whose specific receptors have not been examined in detail thus far. We conducted the prese nt study to determine, by immunocytochemistry and computerized image analys is of the functionalis, the expression and modulation of the receptors Flk- 1/KDR and Flt-1, which mediate VEGF effects on endothelial mitogenicity, ch emotaxis, and capillary permeability. VEGF receptors are expressed mainly i n endometrial endothelial cells, with variations of intensity and number of stained capillaries related to the phase of the cycle. The number of capil laries immunostained for Flk-1/KDR was maximal in the proliferative phase ( ratio Flk-1/CD34: 1), twice as high as the number of Flt-1-expressing capil laries (ratio Flt-1/CD34: 0.47). The staining intensity for Flk-1 decreased during the late proliferative and early secretory phases, to increase agai n in the midsecretory period. The number of Flt-1-labeled capillaries was a bout 2-fold higher in the secretory than in the proliferative phase; howeve r, the proportion of Flt-1-positive cells did not change, owing to the asso ciated increase in vascular density that characterizes progression of the f unctionalis from the proliferative to the secretory stage. The staining int ensity for Flt-1 was higher during the late proliferative and secretory pha ses (especially in the midsecretory phase) and the premenstrual period. In contrast, the proportion of capillaries expressing Flk-1/KDR decreased in t he secretary phase (ratio Flk-1/Von Willebrand factor: 0.55). Enhanced expr ession of Flk-1/KDR, and of Flt-1, on narrow capillary strands at the begin ning of and during the proliferative phase may account for the rapid capill ary growth associated with endometrial regeneration following menstrual she dding. The high coexpression of Flk-1/KDR and Flt-1 observed on capillaries during the midsecretory period: correlates with an increase of endometrial microvascular density and of permeability characteristic of this phase of the cycle, which is a prerequisite for implantation. Finally, strong expres sion of Flt-1, but not Flk-1/KDR, was observed on dilated capillaries durin g the premenstrual period and the late proliferative phase, suggesting pref erential association of Flt-1 with nonproliferating capillaries at those ti mes; activation of this receptor by VEGF could be involved in premenstrual vascular hyperpermeability, edema, and extravasation of leukocytes. In addi tion to the endothelial localization, we found that epithelial cells expres sed Flt-1 and Flk-1/KDR. We conclude that Flt-1 and Flk-1/KDR in the functi onalis are modulated in parallel or independently according to the phase of the cycle, and that these changes are responsible for VEGF actions on endo metrial vascular growth and permeability. The molecular mechanisms concerni ng these regulations will require further investigation.