Vitamin D attenuates cerebral artery remodeling through VDR/AMPK/eNOS dimer phosphorylation pathway after subarachnoid hemorrhage in rats

Abstract

The role of vitamin D3 (VitD3) in the upregulation of osteopontin (OPN) and eNOS in the endothelium of cerebral arteries after subarachnoid hemorrhage (SAH) is investigated. The endovascular perforation SAH model in Sprague-Dawley rats (n = 103) was used. The VitD3 pretreatment (30 ng/kg) increased endogenous OPN and eNOS expression in cerebral arteries compared with naïve rats (n = 5 per group). Neurobehavioral scores were significantly improved in Pre-SAH+VitD3 group compared with the SAH group. The effects of VitD3 were attenuated by intracerebroventricular (i.c.v) injections of siRNA for the vitamin D receptor (VDR) and OPN in Pre-SAH+VitD3+VDR siRNA and Pre-SAH+VitD3+OPN siRNA rats, respectively (n = 5 per group). The significant increase of VDR, OPN and decrease of C44 splicing in the cerebral arteries of Pre-SAH+VitD3 rats lead to an increase in basilar artery lumen. The increase in VDR expression led to an upregulation and phosphorylation of AMPK and eNOS, especially dimer form, in endothelium of cerebral artery. The results provide that VitD3 pretreatment attenuates cerebral artery remodeling and vasospasm through the upregulation of OPN and phosphorylation of AMPK (p-AMPK) and eNOS (p-eNOS) at Ser1177-Dimer in the cerebral arteries. Vitamin D may be a useful new preventive and therapeutic strategy against cerebral artery remodeling in stroke patients.