Signaling via the prostaglandin E2 receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia
Xibin Liang, Lu Lin, Nathaniel S. Woodling, Qian Wang, Christoph Anacker, Tingting Pan, Milton Merchant, Katrin Andreasson
Xibin Liang, Lu Lin, Nathaniel S. Woodling, Qian Wang, Christoph Anacker, Tingting Pan, Milton Merchant, Katrin Andreasson
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Research Article Neuroscience

Signaling via the prostaglandin E2 receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia

Abstract

Stroke is the third leading cause of death in the United States. Fewer than 5% of patients benefit from the only intervention approved to treat stroke. Thus, there is an enormous need to identify new therapeutic targets. The role of inducible cyclooxygenase (COX-2) activity in stroke and other neurologic diseases is complex, as both activation and sustained inhibition can engender cerebral injury. Whether COX-2 induces cerebroprotective or injurious effects is probably dependent on which downstream prostaglandin receptors are activated. Here, we investigated the function of the PGE2 receptor EP4 in a mouse model of cerebral ischemia. Systemic administration of a selective EP4 agonist after ischemia reduced infarct volume and ameliorated long-term behavioral deficits. Expression of EP4 was robust in neurons and markedly induced in endothelial cells after ischemia-reperfusion, suggesting that neuronal and/or endothelial EP4 signaling imparts cerebroprotection. Conditional genetic inactivation of neuronal EP4 worsened stroke outcome, consistent with an endogenous protective role of neuronal EP4 signaling in vivo. However, endothelial deletion of EP4 also worsened stroke injury and decreased cerebral reperfusion. Systemic administration of an EP4 agonist increased levels of activated eNOS in cerebral microvessels, an effect that was abolished with conditional deletion of endothelial EP4. Thus, our data support the concept of targeting protective prostaglandin receptors therapeutically after stroke.

Authors

Xibin Liang, Lu Lin, Nathaniel S. Woodling, Qian Wang, Christoph Anacker, Tingting Pan, Milton Merchant, Katrin Andreasson

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Figure 4

Endothelial EP4 is cerebroprotective.

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Endothelial EP4 is cerebroprotective. (A) Confocal microscopy demonstrat...
(A) Confocal microscopy demonstrated low to undetectable levels of EP4 in control VECad-Cre-ERT2;EP4+/+ and VECad-Cre-ERT2;EP4lox/lox cerebral cortical vasculature at 24 hours after sham surgery. Shown is induction of EP4 expression in VECad-Cre-ERT2;EP4+/+, but not VECad-Cre-ERT2;EP4lox/lox, cerebral cortical vasculature 24 hours after MCAo. 4 hours after MCAo, EP4 expression was upregulated in endothelium and colocalized with Factor VIII and with β-dystroglycan (Supplemental Figure 8, A and B). Scale bar: 20 μm. (B) Male mice were subjected to 30 minutes of MCAo, and infarct volumes were quantified at 24 hours in cresyl violet–stained brain sections. Infarct size was increased in both VECad-Cre-ERT2;EP4lox/+ and VECad-Cre-ERT2;EP4lox/lox mice compared with control VECad-Cre-ERT2;EP4+/+ mice. Body temperature and physiological measurements did not differ between genotypes (Supplemental Figure 9B and Supplemental Table 1). *P ≤ 0.05. (C) AE1-329 administration (0.3 mg/kg 3 hours after MCAo) reduced infarct size in VECad-Cre-ERT2;EP4lox/lox male mice subjected to 45 minutes MCAo followed by 23 hours of reperfusion. *P < 0.05. In B and C, numerals within bars denote n in each group.