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Updated: Aug 16, 2026
An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
17beta-estradiol, but not raloxifene, decreases thrombomodulin in the antithrombotic protein C pathway
M A Richardson1, D T Berg, D S Calnek
1Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Abstract:
Raloxifene is a nonsteroidal selective estrogen receptor modulator (SERM) that mimics the effects of estrogen on some plasma lipids and may have direct effects on the vascular wall. The objective of this study was to determine the effects of 17beta-estradiol, raloxifene, and LY139,478 (a related benzothiophene SERM) on the anticoagulant protein C pathway. In human vascular endothelial cells activated with interleukin-1 (IL-1), we demonstrated decreased thrombomodulin-dependent protein C activation. 17beta-estradiol reduced the anticoagulant properties of both unstimulated and IL-1-activated endothelial cells by decreasing thrombomodulin expression. In contrast, raloxifene and LY139,478 enhanced the anticoagulant properties of both unstimulated and IL-1-activated endothelial cells through upregulation of thrombomodulin. Regulation of the protein C pathway via thrombomodulin on vascular endothelium may be a novel mechanism by which SERMs could potentially confer cardioprotective effects and reduce the thrombotic risk associated with HRT in compromised patients.
Insights
Selective estrogen receptor modulators (SERMs) like raloxifene enhance anticoagulant properties by upregulating thrombomodulin in endothelial cells, potentially reducing cardiovascular risk.
Area of Science:
- Biochemistry
- Vascular Biology
- Pharmacology
Background:
- Selective estrogen receptor modulators (SERMs) interact with estrogen receptors, influencing various physiological processes.
- Estrogen's effects on plasma lipids and the vascular wall are complex, with implications for cardiovascular health.
- The protein C pathway is a critical regulator of anticoagulation in the vascular system.
Purpose of the Study:
- To investigate the impact of 17beta-estradiol, raloxifene, and LY139,478 on the protein C pathway.
- To determine how these compounds affect thrombomodulin expression and protein C activation in endothelial cells.
- To explore potential cardioprotective mechanisms of SERMs.
Main Methods:
- Utilized human vascular endothelial cells stimulated with interleukin-1 (IL-1).
- Assessed thrombomodulin-dependent protein C activation.
- Quantified thrombomodulin expression levels following treatment with 17beta-estradiol, raloxifene, and LY139,478.
Main Results:
- 17beta-estradiol decreased thrombomodulin expression and reduced anticoagulant properties in endothelial cells.
- Raloxifene and LY139,478 upregulated thrombomodulin expression, enhancing anticoagulant properties.
- Both unstimulated and IL-1-activated endothelial cells showed altered anticoagulant function in response to the tested compounds.
Conclusions:
- SERMs, specifically raloxifene and LY139,478, enhance endothelial anticoagulation by increasing thrombomodulin.
- This thrombomodulin-mediated regulation of the protein C pathway may represent a novel cardioprotective mechanism for SERMs.
- SERMs might offer a reduced thrombotic risk compared to hormone replacement therapy (HRT) in certain patient populations.
