Elucidating the role of pigment epithelium-derived factor (PEDF) in metabolic PCOS models

Abstract

PCOS is the most common endocrinopathy in women; associated with obesity and insulin resistance (IR). IR leads to accumulation of advanced-glycation-end-products (AGEs) and their receptor, RAGE. PCOS patients have increased levels of vascular endothelial growth factor (VEGF), interleukin 6/8 (IL-6/8) and anti-Mϋllerian-hormone (AMH). PEDF is a secreted-glycoprotein known for its anti-angiogenic and anti-inflammatory properties. We aimed to elucidate the role of PEDF in the pathogenesis and treatment of PCOS. We used a prenatal PCOS mouse model and fed the female offspring a high-fat diet, inducing metabolic PCOS (met.PCOS) characteristics. Female offspring were divided into three groups: control; met.PCOS; met.PCOS + recombinant PEDF (rPEDF). Met.PCOS mice gained more weight, had elevated serum IL-6 and higher mRNA levels of AMH, PEDF and RAGE in their granulosa cells (GCs) than met.PCOS + rPEDF mice. An in vitro Met.PCOS model in human GCs (KGN) line was induced by prolonged incubation with insulin/AGEs, causing development of IR. Under the same conditions, we observed an elevation of VEGF, IL-6/8 mRNAs, concomitantly with an increase in PEDF mRNA, intracellular protein levels, and an elevation of PEDF receptors (PEDF-Rs) mRNA and protein. Simultaneously, a reduction in the secretion of PEDF from GCs, was measured in the medium. The addition of rPEDF (5 nM) activated P38 signaling, implying that PEDF-Rs maintained functionality, and negated AGE-induced elevation of IL-6/8 and VEGF mRNAs. Decreased PEDF secretion may be a major contributor to hyperangiogenesis and chronic inflammation, which lie at the core of PCOS pathogenesis. rPEDF treatment may restore physiological angiogenesis inflammatory balance, thus suggesting a potential therapeutic role in PCOS.

AGEs-related dysfunctions in PCOS: evidence from animal and clinical research

“…By using this model, it was demonstrated that VEGF, IL6/8, and PEDF mRNA correlated with hyperangiogenesis and chronic inflammation. Exposure to rPEDF reduced AGE-induced elevation of VEGF and IL6/8 (Silber et al 2020).…”

“…Recently, it has been reported that exposure to five different types of AGEs inhibited the proliferation of primary human granulosa cells and KGN cells in association with luteinizing hormone receptor (LHR) down regulation and reduced secretion of progesterone (Lin et al 2019). Silber et al (2020) proposed an in vitro PCOS model of granulosa cells based on prolonged incubation of KGN granulosa cells with insulin/AGEs. By using this model, it was demonstrated that VEGF, IL6/8, and PEDF mRNA correlated with hyperangiogenesis and chronic inflammation.…”

“…In a mouse model obtained by prenatal exposure to dihydrotestosterone (DHT) and post-natal high-fat diet, it was demonstrated that a therapy based on metformin in association with rPEDF was effective in controlling weight gain and reducing ovarian follicle RAGE and inflammatory status (Silber et al 2020).…”

Pigment epithelium‐derived factor negates oxidative stress in mouse oocytes

“…Our laboratory showed that several female hormones control its endogenous regulation in the ovary, under physiologic conditions and suggested that PEDF basal production is high, thus maintaining the essential angiogenic and inflammatory balance within the ovary. 45 We further examined the association of PEDF with reproduction-related syndromes, and demonstrated that rPEDF has a beneficial effect in cases of endometriotic lesions, 29 OHSS, 30,46 metabolic PCOS 47 and uterine fibrosis. 48 Additionally, we demonstrated, that PEDF negates OS in granulosa cells.…”

Mechanical stress-induced Hippo signaling in respect to primordial follicle development and polycystic ovary syndrome pathogenesis

“…Although an indirect relationship exists between GCT and PCOS, the mechanism underlying hyperandrogenism may be explained by the fact that reduced CYP19A1 expression and impaired estrogen production result in the corresponding overproduction of androgen. Furthermore, accumulated knowledge has shown that patients with PCOS are at increased risk of developing insulin resistance (IR) [29][30][31][32] . Thus, the links between the transcriptional co-activator YAP/ TAZ and IR need to be clarified.…”