PGE2 promotes angiogenesis through EP4 and PKA Cγ pathway.

Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE

Publication: 2021- : [New York] : Elsevier
Original Publication: New York, Grune & Stratton [etc.]

Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/*physiology ; Dinoprostone/*physiology ; Neovascularization, Physiologic/*physiology ; Receptors, Prostaglandin E, EP4 Subtype/*physiology; Animals ; Aorta, Thoracic/cytology ; Aorta, Thoracic/drug effects ; Aorta, Thoracic/physiology ; Base Sequence ; Chick Embryo ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/antagonists & inhibitors ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics ; Dinoprostone/pharmacology ; Endothelial Cells/cytology ; Endothelial Cells/drug effects ; Endothelial Cells/physiology ; Gene Knockdown Techniques ; Humans ; In Vitro Techniques ; Mice ; Mice, Inbred C57BL ; Neovascularization, Physiologic/drug effects ; RNA, Small Interfering/genetics ; Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors ; Receptors, Prostaglandin E, EP4 Subtype/genetics

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.

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R01 CA129155 United States CA NCI NIH HHS; CA129155 United States CA NCI NIH HHS

0 (RNA, Small Interfering)
0 (Receptors, Prostaglandin E, EP4 Subtype)
EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Catalytic Subunits)
EC 2.7.11.11 (protein kinase A Cgamma)
K7Q1JQR04M (Dinoprostone)

Date Created: 20110920 Date Completed: 20120103 Latest Revision: 20211020

20250114

PMC3217416

10.1182/blood-2011-04-350587

21926356