Endothelial mineralocorticoid receptor activation enhances endothelial protein C receptor and decreases vascular thrombosis in mice

Abstract

Previous studies have shown that aldosterone, which activates the mineralocorticoid receptor (MR), promotes thrombosis in animal models. Our objective was to determine whether MR activation/expression in the vascular endothelium could modify thrombotic risk in vivo and to examine thrombin generation at the surface of aortic endothelial cells (HAECs). MR was conditionally overexpressed in vivo in vascular endothelial cells in mice (MR-EC mice) or stimulated with aldosterone in HAECs. Thrombosis after ferric chloride injury was delayed in MR-EC mice compared with controls as well as in wild-type FVB/NRj mice treated with aldosterone (60 μg/kg/d for 21 d). Thrombin generation in platelet-poor plasma did not differ between MR-EC mice and controls. In MR-EC mice, aortic endothelial cell protein C receptor (EPCR) expression was increased. Aldosterone (10(-8) M) attenuated thrombin generation at the surface of cultured HAECs, and this effect was associated with up-regulation of expression of EPCR, which promotes formation of activated protein C. Aldosterone increases EPCR expression via a transcriptional mechanism involving interaction of MR with the specificity protein 1 site. These findings demonstrate that MR activation acts on endothelial cells to protect against thrombosis in physiological conditions and that MR-mediated EPCR overexpression drives this antithrombotic property through enhancing protein C activation.

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…Another recent issue is the involvement of MR signaling in vascular thrombosis. In mice with arterial injury or in normotensive rats, aldosterone was reported to favor thrombosis, whereas MR overexpression in endothelium impaired thrombus formation (Lagrange et al, 2014). Endothelial MR activation may have a beneficial antithrombotic action in healthy vessels, whereas deleterious prothrombotic effects may occur only when the endothelium is injured (Lagrange et al, 2014).…”

“…In a rat model of endotoxin-induced uveitis, intraocular injection of aldosterone reduced the clinical intensity of the early phase of uveitis and restored the downregulated MR brought on by inflammation in the iris and ciliary body . Activation of MR appears to have anticoagulant properties in mice with intact endothelium (Lagrange et al, 2014). Thus, although MR activation is generally considered as detrimental, it is important to realize that this pathway may be beneficial in some specific pathologic situations.…”

Mineralocorticoids in the Heart and Vasculature: New Insights for Old Hormones

“…After ferric chloride injury, a less invasive model that leaves the endothelial layer intact, mice overexpressing MR in endothelial cells were protected against thrombosis formation (155). MR is also expressed in venous tissue, and vein graft remodeling in mice was prevented by spironolactone treatment (156).…”

Mineralocorticoid receptors in the heart: lessons from cell-selective transgenic animals

“…Interestingly, MR signalling specifically in endothelial cells has recently been shown to reduce atrial thrombus formation in mice overexpressing MR conditionally in endothelial cells (Lagrange et al 2014). The authors propose a hypothesis that aldosterone-activated endothelial cell MR possesses antithrombotic properties in healthy vessels, while aldosterone acts synergistically with endothelial injury to exert prothrombotic effects (Newfell et al 2011).…”