Placenta Growth Factor (PlGF), a Novel Inducer of Plasminogen Activator Inhibitor-1 (PAI-1) in Sickle Cell Disease (SCD)

Abstract

Sickle cell disease (SCD) is characterized by a prothrombotic state. Plasminogen activator inhibitor-1 (PAI-1) is known to modulate fibrinolysis, lung injury/fibrosis, and angiogenesis. However, its role in SCD is less understood, and the molecular mechanisms underlying increased PAI-1 are unknown. Herein, we show a novel link between PAI-1 and sickle erythropoiesis. Plasma PAI-1 levels were high in SCD patients at steady state and in two humanized sickle mouse models, with increased PAI-1 immunolabeling in sickle mouse lung, bronchial epithelial cells, alveolar macrophages, and pulmonary microvascular endothelial cells. Placenta growth factor (PlGF), released at high levels by sickle erythroblasts, induced PAI-1 expression in primary human pulmonary microvascular endothelial cells and monocytes through activation of c-Jun N-terminal kinase (JNK), NADPH oxidase, and hypoxia-inducible factor-1␣ (HIF-1␣). Analysis of the human PAI-1 promoter revealed this induction was mediated by hypoxia-response element (HRE)-1, HRE-2, and distal activator protein (AP-1) sites. We also identify the involvement of c-Jun, c-Jun/c-Fos, and JunD, but not JunB, in binding with AP-1 sites of the PAI-1 promoter upon PlGF induction. Consistent with these findings, levels of PAI-1 were low in PlGF knock-out mice and sickle-PlGF knock-out mice; overexpression of PlGF in normal mice increased circulating PAI-1. In conclusion, we identify a novel mechanism of PAI-1 elevation in SCD.

Key endothelial cell angiogenic mechanisms are stimulated by the circulating milieu in sickle cell disease and attenuated by hydroxyurea

“…While evidence supports the existence of an elevated production of pro-angiogenic factors in SCD, [12][13][14][15]31,32 few studies are available to establish a clear link between angiogenic factor production and pathological neovascularization in this disease. High levels of stromal-derived factor-1, augmented PlGF and discretely elevated PDGF-BB have been associated with pulmonary hypertension or high tricuspid regurgitation velocity in SCD, 13,16,19 while increased pigment epithelium-derived factor has been related to SCD retinopathy.…”

Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ

“…Placenta growth factor (PIGF) induces expression of PAI-1 in Sickle cell disease (Patel et al, 2010). In this process, PIGF induces binding of AP-1 to PAI-1 promoter sequences.…”

Peroxisome Proliferator-activated Receptor-α-mediated Transcription of miR-199a2 Attenuates Endothelin-1 Expression via Hypoxia-inducible Factor-1α

“…BK-SS mice originally obtained from Jackson Laboratories were bred up to the sixth generation against a C57BL/6NJ background. BK-SS mice carry deletions for the mouse ␣-and ␤-globin genes and carry a transgene expressing the human ␣-globin and a mini ␤-globin cluster including ␤-sickle globin (26,27). In-house bred C57BL/6NJ animals served as controls.…”