Investigation of the Effects of Estrogen on Von Willebrand Factor Regulation

Abstract

Von Willebrand factor plays a critical role in primary hemostasis, with circulating levels known to rise during pregnancy to mitigate the risk of postpartum hemorrhage. Estrogen is often cited as a key hormonal driver of this increase, yet its direct role in regulating VWF remains poorly defined and largely uninvestigated in isolation from the broader physiological changes of pregnancy. This study aimed to determine the effects of the primary female pregnancy hormones, estrogen and progesterone, on VWF regulation in comparison to the physiological changes observed during murine pregnancy. Pregnant C57Bl/6 mice were monitored for hormone and VWF:Ag changes across gestation. To dissect hormone-specific effects, ovariectomized mice were treated with estradiol, progesterone, or both. Human umbilical vein endothelial cells were also used to explore receptor expression and direct hormonal modulation of VWF. Despite significantly increasing VWF transcription and protein expression in both lung and liver tissue, estradiol treatment paradoxically reduced circulating VWF:Ag levels. In contrast, VWF:Ag levels increased steadily throughout pregnancy, peaking near term. This discrepancy was associated with a marked upregulation of VWF clearance receptors, including SR-A1, MGL2, and SCARA5, in estradiol-treated mice, which was not observed in late pregnancy. In vitro, HUVECs expressed the estrogen receptors ERβ and GPER1 and increased VWF protein production directly in response to estradiol. These findings reveal a novel, potentially clearance-driven mechanism by which estradiol reduces circulating VWF levels, challenging long-held assumptions about its hemostatic role and highlighting critical gaps in our understanding of hormone-driven regulation of coagulation, with broader implications for women’s health across pregnancy, postpartum, and hormone therapy contexts.