Objective:
We previously reported that sigma-1 receptor (
σ
1
R
) expression in the thoracic aorta decreased after pressure overload (PO) induced by abdominal aortic banding in ovariectomized (OVX) rats. Here, we asked whether stimulation of
σ
1
R with the selective agonist SA4503 elicits functional recovery of aortic vasodilation and constriction following vascular injury
in OVX rats with PO.
Methods:
SA4503 (0.3-1.0 mg kg
-1
) and NE-100 (an
σ
1
R
antagonist, 1.0 mg kg
-1
) were administered orally for 4 weeks (once daily) to OVX-PO rats, starting from the onset of aortic banding. Vascular functions of isolated descending aorta were measured following phenylephrine (PE)- or endothelin-1 (ET-1)-induced vasoconstriction and acetylcholine (ACh)- or clonidine-induced vasodilation.
Results:
σ
1
R
expression in aortic smooth muscle and endothelial cells decreased significantly 4 weeks after PO in OVX rats (vs. Sham or OVX only group). SA4503 administration rescued PO-induced
σ
1
R decreases in the
descending aorta. SA4503 treatment also rescued PO-induced impairments in ACh- and clonidine-induced vasodilation without affecting PE- and ET-1-induced vasoconstriction. Ameliorated ACh- and clonidine-induced vasodilation was closely associated with increased Akt activity and in turn endothelial nitric oxide synthase (eNOS) phosphorylation. SA4503-mediated improvement of vasodilation was blocked by NE-100 treatment.
Conclusions:
σ
1
R
is downregulated following PO-induced endothelial injury in OVX rats. The selective
σ
1
R
agonist SA4503 rescues impaired endothelium-dependent vasodilation in the aorta from OVX-PO rats through
σ
1
R
stimulation, enhancing eNOS-cGMP signaling in vascular endothelial cells. These observations encourage development of novel therapeutics targeting
σ
1
R
to prevent vascular endothelial injury in postmenopausal woman.
Dehydroepiandrosterone-Mediated Stimulation of Sigma-1 Receptor Activates Akt-eNOS Signaling in the Thoracic Aorta of Ovariectomized Rats with Abdominal Aortic Banding