Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1

Abstract

Placenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.

The Anti-Vascular Endothelial Growth Factor Receptor 1 (VEGFR-1) D16F7 Monoclonal Antibody Inhibits Melanoma Adhesion to Soluble VEGFR-1 and Tissue Invasion in Response to Placenta Growth Factor

“…Detection of growth factor levels was performed using a DuoSet ® mouse PlGF-2 kit (Cat No. DY465, R&D Systems) following the manufacturer’s instructions [ 29 ]. Optical density was measured at 450 nm (reference wavelength, 540 nm) in a microplate reader (Infinite F50, Tecan).…”

Cardiovascular complications in insulin resistance and endocrine diseases

“…When growth factors such as insulin activate Akt, FoxOs is phosphorylated in the nucleus and translocated to the nuclear envelope, where it becomes inactive as a transcription factor. Moreover, hyperglycemia is also reported to directly increase FoxOs activity by decreasing phosphorylation in cultured human aortic [28] and umbilical vein endothelial cells [47].…”

Metformin in cardiovascular diabetology: a focused review of its impact on endothelial function

“…It is speculated that endoglin is involved in the regulation of ED, and oxidative stress may play a role in this regulation 83 . Through suppression of phosphatidylinositol 3 kinase (PI3K)-Akt signalling and activation of FOXO1 in cultured primary endothelial cells, hyperglycemia stimulated placenta growth factor (PlGF) secretion which is a pro-inflammatory angiogenic mediator 84 . Hyperglycemia drives ED via different mechanisms, including excessive oxidative stress, over activated inflammation and reduced NO bioavailability (see Figure 2 ).…”