PGE2 promotes angiogenesis through EP4 and PKA Cγ pathway
- 10 November 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 118 (19), 5355-5364
- https://doi.org/10.1182/blood-2011-04-350587
Abstract
Inflammation is increasingly recognized as a critical mediator of angiogenesis, and unregulated angiogenic response is involved in human diseases, including cancer. Proinflammatory prostaglandin E2 (PGE2) is secreted by many cell types and plays important roles in the process of angiogenesis via activation of cognate EP1-4 receptors. Here, we provide evidence that PGE2 promotes the in vitro tube formation of human microvascular endothelial cells, ex vivo vessel outgrowth of aortic rings, and actual in vivo angiogenesis. Use of EP subtype-selective agonists and antagonists suggested EP4 mediates the prostaglandin-induced tube formation, and this conclusion was substantiated with small interfering RNA to specifically knockdown the EP4 expression. EP4 couples to Gαs, leading to activation of protein kinase A (PKA). Inhibition of PKA activity or knockdown of PKA catalytic subunit γ with RNAi attenuates the PGE2-induced tube formation. Further, knocking down the expression of Rap1A, HSPB6, or endothelial NO synthase, which serve as PKA-activatable substrates, inhibits the tube formation, whereas knockdown of RhoA or glycogen synthase kinase 3β that are inactivated after phosphorylation by PKA increases the tube formation. These results support the existence of EP4-to-PKA angiogenic signal and provide rationale for use of selective EP4 signal inhibitors as a probable strategy to control pathologic angiogenesis.Keywords
This publication has 50 references indexed in Scilit:
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Small heat shock protein 20 (HspB6) in cardiac hypertrophy and failureJournal of Molecular and Cellular Cardiology, 2010
- PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targetsProceedings of the National Academy of Sciences of the United States of America, 2010
- A global map of human gene expressionNature Biotechnology, 2010
- Eicosanoids and cancerNature Reviews Cancer, 2010
- Immune cells and angiogenesisJournal of Cellular and Molecular Medicine, 2009
- Anti‐angiogenic and vascular disrupting effects of C9, a new microtubule‐depolymerizing agentBritish Journal of Pharmacology, 2009
- Rap1a Is a Key Regulator of Fibroblast Growth Factor 2-Induced Angiogenesis and Together with Rap1b Controls Human Endothelial Cell FunctionsMolecular and Cellular Biology, 2008
- Vascular Abnormalities in Mice Deficient for the G Protein-Coupled Receptor GPR4 That Functions as a pH SensorMolecular and Cellular Biology, 2007
- Seminal plasma and prostaglandin E2 up-regulate fibroblast growth factor 2 expression in endometrial adenocarcinoma cells via E-series prostanoid-2 receptor-mediated transactivation of the epidermal growth factor receptor and extracellular signal-regulated kinase pathwayHuman Reproduction, 2006