HDAC5 inhibits ovarian angiogenesis in dehydroepiandrosterone-induced mouse model of polycystic ovary syndrome
Abstract
Introduction. Abnormal ovarian angiogenesis is a common feature of polycystic ovary syndrome (PCOS), a typical endocrine disorder affecting women of reproductive age. Histone deacetylase 5 (HDAC5) has been documented as a suppressor of angiogenesis. The aim of this study was to explore the effect of HDAC5 on ovarian angiogenesis in a PCOS mouse model.
Material and methods. PCOS was induced in female C57BL/6 mice by 20-day administration of dehydroepiandrosterone (DHEA). HDAC5 was over-expressed in PCOS mice by corresponding adenovirus injection. In total, 120 mice were used in this study. Western-blotting, real-time PCR, hematoxylin and eosin staining, enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining, flow cytometry, and co-immunoprecipitation were respectively used to evaluate the effect of HDAC5 on PCOS mice.
Results. PCOS ovaries showed a compensatory increase in HDAC5 expression, while HDAC5 over-expression alleviated abnormalities in ovarian morphology and serum hormone levels after PCOS modeling. HDAC5 inhibited ovarian angiogenesis in PCOS mice by regulating angiogenesis-related factors, such as VEGFA, platelet-derived growth factors B and D (PDGFB/D), and angiopoietins 1 and 2 (ANGPT1/2) and CD31. HDAC5 over-expression decreased levels of reactive oxygen species (ROS) and malondialdehyde, while promoting activities of catalase and superoxide dismutase in ovaries of PCOS mice, suggesting its suppressive effects on oxidative stress, an inducer of uncontrolled angiogenesis. Moreover, HDAC5 suppressed activation of angiogenesis-related HIF-1α/VEGFA/VEGFR2 signaling in PCOS ovaries partly via inhibiting VEGFR2 acetylation.
Conclusions. This study reveals the protective role of HDAC5 in PCOS by inhibiting ovarian angiogenesis and provides a molecular candidate for PCOS therapy in the future.
Keywords: mousepolycystic ovary syndromeHDAC5 overexpressionangiogenesisoxidative stress
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