Estradiol inhibits vascular endothelial cells pro-inflammatory activation induced by C-reactive protein

Abstract

In addition of being an important inflammatory biomarker and a risk factor for cardiovascular disease, much evidence indicates that the C-reactive protein (CRP) contributes to the atherosclerosis development process. This plasmatic protein synthesized by hepatocytes in response to inflammation and tissue injury induces pro-inflammatory molecules' expression by endothelial cells (ECs). Previous studies showed that the 17β-estradiol (E2) has beneficial effects on vascular cells by reducing in vitro pro-inflammatory molecules expressions in EC. Therefore, we hypothesize that E2 blocks or reduces CRP-mediated inflammatory responses by modulating endogenous production of CRP in EC and/or activation mechanisms. Using human aortic ECs (HAECs), we first evaluated CRP production by vascular EC and second demonstrated its self-induction. Indeed, recombinant human CRP stimulation induces a fivefold increase of CRP expression. A 1-h pre-treatment of E2 at a physiologic dose (10⁻⁹ M) leads to an important decrease of CRP production suggesting a partial blockage of its amplification loop mechanism. Furthermore, in HAEC, E2 reduces the secretion of the most potent agonist of CRP induction, the IL-6, by 21 %. E2 pre-treatment also decreased the expression of pro-inflammatory molecules IL-8, VCAM-1, and ICAM-1 induced by CRP and involved in leukocytes recruitment. In addition, we demonstrated that E2 could restore vascular endothelial growth factor-mediated EC migration response impaired by CRP suggesting another pro-angiogenic property of this hormone. These findings suggest that E2 can interfere with CRP pro-inflammatory effects via activation signals using its rapid, non-genomic pathway that may provide a new mechanism to improve vascular repair.

 

Conclusion

Thus, in this study, we demonstrate that EC could express CRP and be a site for CRP self-induction. We illustrate a process of positive feedback production of the protein by vascular cells that could lead to the marked local increase concentration reported in atherosclerotic plaques. Furthermore, the present study highlights a novel vasoprotective role of E2 in the inhibition of this endogenous CRP self-induction, altering its pro-inflammatory activities in vascular EC by a non-genomic pathway. By exploring the angiogenic potential of E2, our study demonstrates for the first time that this hormone restores EC migration altered by CRP. Further investigation will be needed to clarify mechanisms of E2 vascular protection by negative regulation of important proatherogenic inflammatory pathways controlled by CRP