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

Abstract

Angiogenesis is fundamental for human endometrial development and differentiation 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 present study to determine, by immunocytochemistry and computerized image analysis of the functionalis, the expression and modulation of the receptors FIk-1/KDR and FIt-1, which mediate VEGF effects on endothelial mitogenicity, chemotaxis, and capillary permeability. VEGF receptors are expressed mainly in endometrial endothelial cells, with variations of intensity and number of stained capillaries related to the phase of the cycle. The number of capillaries immunostained for FIk-1/KDR was maximal in the proliferative phase (ratio FIk-1/CD34: 1), twice as high as the number of FIt-1-expressing capillaries (ratio FIt-1/CD34:0.47). The staining intensity for FIk-1 decreased during the late proliferative and early secretory phases, to increase again in the midsecretory period. The number of FIt-1-labeled capillaries was about 2-fold higher in the secretory than in the proliferative phase; however, the proportion of FIt-1-positive cells did not change, owing to the associated increase in vascular density that characterizes progression of the functionalis from the proliferative to the secretory stage. The staining intensity for FIt-1 was higher during the late proliferative and secretory phases (especially in the midsecretory phase) and the premenstrual period. In contrast, the proportion of capillaries expressing FIk-1/KDR decreased in the secretory phase (ratio FIk- 1/Von Willebrand factor: 0.55). Enhanced expression of FIk-1/KDR, and of FIt- 1, on narrow capillary strands at the beginning of and during the proliferative phase may account for the rapid capillary growth associated with endometrial regeneration following menstrual shedding. The high coexpression of FIk-1/KDR and FIt-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 expression of FIt1, but not FIk-1/KDR, was observed on dilated capillaries during the premenstrual period and the late proliferative phase, suggesting preferential association of FIt-1 with nonproliferating capillaries at those times; activation of this receptor by VEGF could be involved in premenstrual vascular hyperpermeability, edema, and extravasation of leukocytes. In addition to the endothelial localization, we found that epithelial cells expressed FIt-1 and FIk-1/KDR. We conclude that FIt-1 and FIk-1/KDR in the functionalis are modulated in parallel or independently according to the phase of the cycle, and that these changes are responsible for VEGF actions on endometrial vascular growth and permeability. The molecular mechanisms concerning these regulations will require further investigation.