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.

Abstract

In the uterus, estrogen causes a rapid increase in microvascular permeability, followed later by growth of the endometrium, including the richly vascular stroma. Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF or VEG/PF) is an angiogenic protein that is not only a specific mitogen for endothelial cells, but also a potent stimulator of microvascular permeability. Because of these properties, it seems likely that VEG/PF might mediate estrogen-induced increases in 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 alternatively spliced and gives rise to three transcripts coding for proteins of 188, 164, and 120 amino acids, which, in turn, form the active dimeric factors. Transcripts for VEG/PF mRNAs were detected in the uterus of the rat by reverse transcription-polymerase chain reaction. The mRNAs for the VEG/PF164 and VEG/PF120 subunits were the dominant forms expressed. Treatment with both estradiol (E2) and estriol (E3) rapidly induced an increase in the level of the two smaller transcripts. The increase 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 control 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 by cycloheximide. The increase occurred as rapidly as that of the mRNA for Zif268, an estrogen-induced transcription factor. Progesterone also stimulated the expression (at 6 h) of VEG/PF164 and VEG/PF120, but not 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-induced increase in permeability and proliferation of uterine blood vessels. The identification of VEG/PF as a primary response gene also suggests that VEG/PF expression may be a prerequisite for the subsequent expression or action of other growth factors in the uterus.

Effect of Low Molecular Weight Heparins (LMWHs) on antiphospholipid Antibodies (aPL) – Mediated Inhibition of Endometrial Angiogenesis

“… Figure 3A summarizes NF-κB and STAT-3 signalling pathways, two intracellular mechanisms independently activated during HEEC angiogenesis [20], [21], [22], [23], [24]. The effects of LMWHs on aPL inhibited NFκB binding activity and activation of STAT-3 in presence of aPL with, or without, LMWHs were evaluated.…”

“…During angiogenesis, a coordinated series of steps allows HEEC to invade, migrate and proliferate into the underlying interstitial matrix and form a new capillary structure [20], [21]. A key player in this process is represented by VEGF whose function is to promote the survival, migration and differentiation of endothelial cells, as well as to mediate vascular permeability [32], [33].…”

Molecular Cloning and Characterization of Mouse EBAG9, Homolog of a Human Cancer Associated Surface Antigen: Expression and Regulation by Estrogen

“…In mouse uterus, the endometrial cells proliferate by estrogen via estrogen receptor (42). The factors driving the cell growth such as c-fos (43), c-jun (44), TGF-␤ (45), VEGF (46), and cyclin D1 (47,48) are known to be regulated by estrogen, and contribute to the cell growth in the uterus. For the cells of vascular smooth muscle (49 -51) and certain kinds of tumor cells (52), on the other hand, estrogen inhibits the cell growth.…”

The Role of Vascular Endothelial Growth Factor in Angiogenesis

“…Subsequently, the blood vessels regress, suggesting the coordinated action of inducers and inhibitors of angiogenesis in the course of the ovarian cycle [56, 57]. Previous studies have shown the VEGF mRNA is temporally and spatially related to the proliferation of blood vessels in the rat, mouse and primate ovary and in the rat uterus [58, 59, 60, 61]. The availability of an effective inhibitor of rodent VEGF, such as a truncated soluble Flt-1 receptor [mFlt(1–3)-IgG], has made it possible to determine the role of VEGF in such processes [62, 63].…”