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Sphingosine-1-phosphate receptors (S1PRs) and their signaling pathways play an important role in mediating vascular health and function. Upon ligand mediated activation, S1PRs 1-5 couple with diverse heterotrimeric G-protein subunits (Gαi, Gαq/11, Gα12/13), initiating multimodal downstream signaling pathways which result in various physiological outcomes in the vasculature, including cell proliferation and migration, barrier integrity preservation or loss, contraction, and inflammation. Specifically, S1PR2 activation has been linked to endothelial activation, barrier integrity loss, and inflammation, whereas S1PR1 activation contributes to barrier integrity preservation, vasodilation, and anti-inflammatory properties. Although the role of S1PRs during pathophysiological conditions such as acute ischemic stroke is under current investigation, the complete S1PR expression profile in the cerebrovasculature following acute ischemic injury has not yet been investigated. Therefore, the present study was aimed to characterize the expression profiles of S1PRs 1-5 in human brain microvascular endothelial cells (HBMECs) and human brain vascular smooth muscle cells (HBVSMCs) following 3h hypoxia plus glucose deprivation (HGD; in vitro ischemic injury) exposure. At the mRNA level, we observed expression of S1PRs 1-5 in HBVSMCs and S1PRs 1-4 in HBMECs. Under basal conditions, we employed real-time RT-PCR and observed that mRNA levels of S1PR1 were highest in expression followed by S1PR3 then S1PR2 in HBMECs. On the other hand, S1PR3 mRNA was the highest followed by S1PR2 then S1PR1 in HBVSMCs. In HBMECs, HGD exposure increased S1PR1 mRNA and protein levels, but decreased S1PR1 mRNA in HBVSMCs. Similarly, HGD induced increased S1PR3 mRNA in HBMECs and decreased S1PR3 mRNA in HBVSMCs. For S1PR2, HGD did not alter mRNA or protein expression in HBMECs but increased mRNA levels in HBVSMCs. These data suggest that acute exposure to HGD appears to differentially regulate expression of S1PRs in HBMECs and HBVSMCs. The differential expression in S1PRs both basally and following HGD exposure may suggest distinct signaling mechanisms at play within the two cerebrovascular cell types, implicating these receptors as potential therapeutic targets following ischemic injury.
In various studies, sumac, a Mediterranean spice and known antioxidant,39,7,66,67 has been shown to have antioxidant properties through its ability to inhibit reactive oxygen species (ROS) such as superoxide.39,7,66,67 Sumac has also been found to reduce TNF-alpha.100 Results from a study of hypertensive human subjects fed a sumac supplement showed a decrease in blood pressure.59
In the current study, COX-2 levels were determined to evaluate the level of inflammation in response to palmitate when primary aortic human vascular smooth muscle cells (HAoVSM) were treated with sumac. The treatments included: vehicle (bovine serum albumin), 100 µM palmitate, and 10, 20, 40, 60, and 80 µg/mL sumac. Sumac did not alter COX-2 protein levels between vehicle and sumac groups. Additional studies were designed to examine whether 80 µg/mL sumac could reverse impaired vasodilation caused by 10 weeks of high fat intake, consisting of 60% of total calories from fat, in Sprague-Dawley rats. Mesenteric arteries were isolated and exposed to sumac. High fat diet (HFD) arteries had impaired vasodilation compared to arteries from chow-fed fats. HFD arteries exposed to sumac had similar endothelium-dependent vasodilation responses as those not exposed to sumac, however, there were trends for improved vasodilation. I suggest that sumac likely exhibits antioxidant capabilities that prevent superoxide from decreasing the bioavailability of nitric oxide in the vasculature, thus promoting endothelium-dependent vasodilation and preventing the creation of more harmful reactive oxygen species. Isolated arteries from chow fed rats developed irreversible vasodilation when exposed to sumac and were therefore not responsive to pre-constriction with phenylephrine (PE) likely related to nitrates and gallic acid naturally present in sumac whereby inhibiting PE.
