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PDE4 regulates tissue plasminogen activator expression of human brain microvascular endothelial cells
Fan Yang1, Shuo Liu, Chuanhui Yu
1Department of Anatomy & Neurobiology, University of California, Irvine, USA.
Introduction:
Factors regulating brain tissue plasminogen activator (tPA) are pertinent for stroke. Recent observations have suggested a role for the phosphodiesterase-4 (PDE4) pathway in stroke pathogenesis, via an uncertain mechanism. We studied PDE4 regulation of tPA expression by human brain microvascular endothelial cells in a variety of conditions, including an in vitro model of ischemia.
Materials And Methods:
We analyzed tPA antigen and mRNA of human brain microvascular endothelial cells (HBECs) during normoxia and oxygen-glucose deprivation (OGD) following inhibition of PDE4 and PDE4D, using HBEC monocultures and co-cultures with astrocytes and pericytes, and analyzed relevant signal transduction pathways.
Results:
PDE4 inhibitor rolipram enhanced OGD effects on endothelial tPA release in endothelial monocultures and co-cultures with astrocytes; there was a 54±10% (p<0.001) reduction of tPA release in astrocyte-endothelial co-cultures under OGD. PDE4D siRNA reduced endothelial tPA mRNA to 40-55% of control (p<0.05). Use of Epac inducer mimicked, while use of Epac siRNA inhibited, these effects.
Conclusions:
Inhibition of PDE4 and PDE4D reduced expression of tPA by HBEC via Epac pathway.
