VASCULAR ENDOTHELIAL GROWTH-FACTOR VASCULAR-PERMEABILITY FACTOR EXPRESSION IN THE RAT UTERUS - RAPID STIMULATION BY ESTROGEN CORRELATES WITH ESTROGEN-INDUCED INCREASES IN UTERINE CAPILLARY-PERMEABILITY AND GROWTH

In the uterus, estrogen causes a rapid increase in microvascular perme ability, followed later by growth of the endometrium, including the ri chly vascular stroma. Vascular endothelial growth factor/vascular perm eability factor (VEGF/VPF or VEG/PF) is an angiogenic protein that is not only a specific mitogen for endothelial cells, but also a potent s timulator of microvascular permeability. Because of these properties, it seems likely that VEG/PF might mediate estrogen-induced increases i n uterine vascular permeability and blood vessel growth. Therefore, we determined whether the gene for VEG/PF is expressed in the rat uterus and if mRNA abundance is regulated by steroid hormones, using reverse transcription-polymerase chain reaction. The VEG/PF gene is alternati vely spliced and gives rise to three transcripts coding for proteins o f 188, 164, and 120 amino acids, which, in turn, form the active dimer ic factors. Transcripts for VEG/PF mRNAs were detected in the uterus o f the rat by reverse transcription-polymerase chain reaction. The mRNA s for the VEG/PF164 and VEG/PF120 subunits were the dominant forms exp ressed. Treatment with both estradiol (E2) and estriol (E3) rapidly in duced an increase in the level of the two smaller transcripts. The inc rease was detectable as early as 0.5-1 h and peaked at 2 h. Levels of the two smaller transcripts then declined, but remained above control levels for 24 h. The degree of stimulation of VEG/PF mRNA levels was 8 -fold at 2 h. VEG/PF188 mRNA levels were higher by 6 h compared to con trol values. The increase in VEG/PF mRNA levels in response to E2 was not contingent upon de novo protein synthesis, as it was not blocked b y cycloheximide. The increase occurred as rapidly as that of the mRNA for Zif268, an estrogen-induced transcription factor. Progesterone als o stimulated the expression (at 6 h) of VEG/PF164 and VEG/PF120, but n ot that of VEG/PF188. We conclude that the VEG/PF gene is expressed in the rat uterus, and that mRNA levels are rapidly enhanced by estrogen . This response suggests that VEG/PF may be involved in the estrogen-i nduced increase in permeability and proliferation of uterine blood ves sels. The identification of VEG/PF as a primary response gene also sug gests that VEG/PF expression may be a prerequisite for the subsequent expression or action of other growth factors in the uterus.