PB0438 - Estrogens increase plasma VWF levels in vivo, at least in part, through enhancement of VWF mRNA expression.

Background: Pregnancy induces a hypercoagulable state, attributed in part to a progressive increase in circulating Von Willebrand Factor (VWF). This increase is correlated with a marked surge in estrogen levels during pregnancy. In vitro studies have suggested that 17β-estradiol (E2) enhances VWF production and secretion. However, the mechanisms responsible for in vivo VWF regulation by estrogen are not well understood.

Aims: To verify whether the elevation of VWF in human pregnancy is recapitulated in C57BL/6 mice, and to elucidate the underlying mechanisms by manipulating E2 levels in this mouse model.

Methods: Two strategies for estrogen alteration were employed in C57BL/6 mice:
i) Pregnant (n=9) and non-pregnant (n=4) mice underwent blood sampling weekly from baseline until term (3 weeks). Before parturition, lung tissue was collected for VWF mRNA quantification. Plasma was analyzed for VWF and E2 by ELISA.
ii) E2 levels in normal mice were manipulated by ovariectomy (n=3), 1.5 mg (n=3) and 10 mg E2 pellet implants (n=3). Sham ovariectomy (n=2) and normal mice (n=3) were used as reference groups. Lung tissue was collected 3 weeks post-surgery for VWF mRNA quantification.

Results: Plasma estradiol levels significantly increased by the second week of pregnancy (1.63-fold). A subsequent increase in basal plasma VWF:Ag (1.76-fold) and VWF mRNA expression (1.34-fold) was seen at term (Figure 1, 2). A similar pattern of dose-dependent enhancement of VWF expression was documented after 3 weeks of E2 pellet implant treatment for low-dose (1.65-fold) and high-dose (1.98-fold) E2-treated mice (Figure 2). Ovariectomy did not significantly alter circulating E2 or VWF expression compared to sham mice, suggesting involvement of non-ovarian E2 sources (Figure 2).

Conclusion(s): These results show that mice, like humans, exhibit progressive elevation of plasma VWF during pregnancy. This increase is accompanied by a parallel enhancement of VWF gene expression, a phenomenon at least in part driven by estrogen-induced transcriptional activity.