Keratinocyte growth factor and vascular endothelial growth factor: Mediators of progesterone action in the uterus and ovary

Abstract

Progesterone plays an important role in mammalian reproduction, but little is known about mediators of its action. In this dissertation I investigated two growth factors that may mediate progesterone's action in two critical target tissues - keratinocyte growth factor (KGF) in the mouse uterus and vascular endothelial growth factor (VEGF) in the rat ovary. Under the influence of progesterone, the mouse uterine epithelium undergoes dramatic remodeling during the estrous cycle and pregnancy. KGF-KGFR signaling plays a role in mesenchymal-epithelial cell communication in a variety of tissues. I examined the expression of KGFR, and its known ligands in the mouse uterus by RT-PCR. I found that KGFR, KGF, FGF-1, and FGF-10, but not FGF-3 are expressed. Uterine mRNA levels for KGFR and aFGF did not vary with hormone treatment. However, KGF mRNA expression increased coincident with the preovulatory progesterone surge and decreased with estrogen treatment. In contrast, FGF-10 expression increased in the post-ovulatory period and was unaffected by estrogen treatment. These findings suggest that KGF and FGF-10 play a role in steroid-induced remodeling of the mouse uterus. To study the role of KGFR signaling, a transgenic mouse was produced with a dominant-negative mutant KGFR targeted to be expressed in the uterus. Expression of the transgene could not be demonstrated in the uterus, however, and no conclusions can be drawn from our experiments on the role of uterine KGFR signaling. In the rat, a preovulatory surge of progesterone is essential for ovulation. Just prior to ovulation, the follicle swells with edema, monocytes infiltrate, and the follicle wall is broken down by plasmin and collagenases. VEGF expression has also been observed to increase subsequent to the preovulatory progesterone surge and may mediate these ovulatory events. I examined the expression of VEGF in the rat ovary by RT-PCR. Inhibition of the preovulatory progesterone surge inhibited both ovulation and VEGF mRNA expression in the rat. Progesterone appears to act via its receptor to induce VEGF mRNA expression, as treatment with a progesterone receptor antagonist also suppressed VEGF expression. The correlation of VEGF expression and ovulation suggests that VEGF plays a role in ovulation in the rat.