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PGE2 -induced migration of human brain endothelial cell is mediated though protein kinase A in cooperation of EP receptors.

Journal of leukocyte biology (2019-03-06)
Gausal A Khan, Saumya Bhagat, Md Iqbal Alam

PGE2 plays a critical role in angiogenesis, ischemic, and neuro-inflammatory disorders of the brain, which breakdown the blood-brain barrier (BBB). However, the effects of PGE2 on human brain endothelial cell (HBECs) migration, a key process in the angiogenic response and BBB stability, are not well defined. In this study, we investigated the mechanism of PGE2 in HBECs migration in vitro. Here we showed that PGE2 stimulated migration of HBECs in a dose-time and matrix-dependent manner, evaluated by the Boyden chamber assay, but other prostanoids failed to do so. PGE2 receptor (EP2; butaprost), EP3 (sulprostone), and EP4 (PGE1 -OH) receptor agonists stimulated HBECs migration, but the silencing of EP significantly attenuated this effect. EP1 agonist (11-trinor PGE1 ) had no effect on HBECs migration on silencing of the EP1 receptor. We further showed that PGE2 stimulated cAMP production and activated protein kinase A (PKA), whereas pretreatment with the adenyl cyclase inhibitor (dideoxyadenosine; 1 μM) or PKA inhibitors, H89 (0.5 μM)/PKAI (1 μM), completely abrogated PGE2 -induced migration. Furthermore, silencing of the EP2/EP4 receptors significantly inhibited PGE2 -induced cAMP and PKA activation, whereas EP3 receptor silencing failed to do so. These results suggest that PGE2 regulates HBEC migration via cooperation of EP2, EP3, and EP4 receptors. Coupling of PGE2 to these receptors resulted in increased production of cAMP, which regulates HBEC migration via PKA pathway. The elucidation of molecular events involved is critical for the development of targeted strategies to treat cerebrovascular diseases associated with dysregulated angiogenesis.

Product Number
Product Description

Adenosine 5′-triphosphate disodium salt hydrate, Grade I, ≥99%, from microbial
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, purified immunoglobulin, buffered aqueous solution
Fibronectin bovine plasma, powder, BioReagent, suitable for cell culture
Protein Kinase A Inhibitor Fragment 6-22 amide, ≥97% (HPLC)
AH6809, ≥98%, crystalline solid or supercooled liquid

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