Prostaglandin E ₂ Primes the Angiogenic Switch via a Synergic Interaction With the Fibroblast Growth Factor-2 Pathway

Abstract

Rationale: Prostaglandin (PG)E 2 exerts temporally distinct actions on blood vessels, immediate vasodilatation, and long-term activation of angiogenesis. Objective: To study the mechanism of PGE 2 induction of angiogenesis, we characterized its effect on fibroblast growth factor (FGF) Key Words: prostaglandin E 2 Ⅲ angiogenesis Ⅲ fibroblast growth factor-2 Ⅲ fibroblast growth factor receptor type1 Ⅲ inflammation P rostaglandin (PG)E 2 , originally discovered along with other prostanoids for its action on blood vessels, 1 is widely recognized as a mediator of inflammation, capable of recruiting proinflammatory cells and causing pain. In the last decade, PGE 2 has acquired the profile of promoter of tumorigenesis because of its causal association with tumor growth. 2 Lately, PGE 2 and its synthesizing enzyme cyclooxygenase (COX)-2 have been implicated in the control of tumor invasion, a process they accomplish in cooperation with selected gene products present in primary tumors. 3 The PGE 2 protumorigenic action has been attributed to its ability to activate the angiogenic switch, a process which leads to neovessel formation in tumors and which has been documented to be crucial for their continuous growth and propensity to metastasize. 4 The angiogenic switch, a term coined by Folkman and Hanahan, defines an event finalized to activate the vascular endothelium and to produce sprouting from preexisting vessels. 5 Although, the angiogenic switch concept has advanced our understanding of tumor biology, its operational mechanism remains poorly delineated in terms of molecules, intracellular signaling and controls involved.-As part of the renewed interest on the vascular actions exerted by PGE 2 , we have recently shown that the interaction of the prostanoid with its EP3 receptor subtype, induces the angiogenic phenotype by activating the fibroblast growth factor receptor type 1 (FGFR1) pathway in microvascular endothelial cells. 6 Several layers of complexity characterize the underlying mechanism of this activation. It involves, first, the EP3-mediated intracellular stimulation of the tyrosine kinase cSrc, which produces shedding of extracellular matrix-bound fibroblast growth factor (FGF)-2 via activation of metallo-proteases, and finally the interaction of the free ligand, FGF-2, with its receptor, FGFR1. Thus, the basis for PGE 2 -induced angiogenesis lies on the excitation of the FGF-2/FGFR1 pathway, primarily designed to maintain viability of the endothelium.

Akt-Activated Endothelium Constitutes the Niche for Residual Disease and Resistance to Bevacizumab in Ovarian Cancer

“…We investigated the molecular events underlying the potential mechanisms of resistance through FGF2 expression in endothelial cells. As previously reported (28), endothelial FGF2 synthesis is regulated by a signaling cascade involving ERK1/2 and STAT3 activation. Under bevacizumab treatment, FGF2/FGFR1 axis mediates Src activation and downstream activation of the proangiogenic ERK1/2-STAT3 signaling pathway as shown by the increase phosphorylation of Src (Y416), STAT3, and ERK1/2 (Fig.…”

12/15-Lipoxygenase gene knockout severely impairs ischemia-induced angiogenesis due to lack of Rac1 farnesylation

“…9 In the past several years, work from various laboratories including ours had revealed that eicosanoids, the oxygenated metabolites of arachidonic acid (AA) influence angiogenesis. [10][11][12][13][14][15][16][17] Reinforcement of a role for eicosanoids in the regulation of angiogenesis can also be drawn by the demonstrations that while -6 polyunsaturated fatty acids (-6 PUFA) promote angiogenesis, -3 PUFA suppresses these effects. 18,19 In this aspect, it was shown that cytosolic phospholipase A 2 (cPLA 2 ) that liberates AA from the sn-2 position of glycerophospholipids, exerts a positive effect on the regulation of angiogenesis.…”

“…20 Furthermore, numerous studies have shown that cyclooxygenase, lipoxygenase and cytochrome P450 monooxygenase, the 3 pathways by which AA converts into various eicosanoids, are linked to regulation of both embryonic and pathologic angiogenesis. [10][11][12][13][14][15][16][17]21,22 In gaining more insight into the mechanisms of eicosanoid-induced angiogenesis, we have shown that 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), the major product of AA metabolism via the 15-Lox, possesses the capacity to stimulate various signaling molecules, including Src, phosphatidylinositol 3-kinase (PI3K), Akt, MAP kinase/ERK kinase 1 (MEK1), and c-Jun N-terminal kinase 1 (JNK1) leading to activation of transcriptional factors such as activating transcriptional factor 2 (ATF2), activator protein 1 (AP1), early growth response factor 1 (Egr1), and signal transducers and activators of transcription (STATs) and thereby influencing the expression of angiogenic molecules such as fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF) and IL-8 and promoting autocrine-mediated angiogenesis 11-15, 17, 23-25 . Among the signaling molecules that are robustly and sustainably activated by 15(S)-HETE in microvascular endothelial cells of various vascular beds are Src, a non-receptor tyrosine kinase 24 and Rac1, a Rho GTPase.…”

Inhibition of Hypoxia Inducible Factor-1α by Dihydroxyphenylethanol, a Product from Olive Oil, Blocks Microsomal Prostaglandin-E Synthase-1/Vascular Endothelial Growth Factor Expression and Reduces Tumor Angiogenesis

“…The PGE-2 protumorigenic action has been attributed to its ability to promote both tumor growth and the angiogenic process (7,8). We recently showed a synergistic interaction between PGE-2 angiogenic action and the activation of the fibroblast growth factor-2 proangiogenic signaling pathway in endothelial cells (9). PGE-2 is synthesized by three different PGE-synthases (PGEs): one cytosolicPGEs (cPGEs) and two microsomalPGEs (mPGEs-1 and mPGEs-2), which differ in intracellular localization, expression, and activity (10).…”