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Mineralocorticoid receptor negatively regulates angiogenesis through repression of STAT3 activity in endothelial cells
Author(s) -
Zheng XiaoJun,
Liu Yuan,
Zhang WuChang,
Liu Yan,
Li Chao,
Sun XueNan,
Zhang YuYao,
Xu Jie,
Jiang Xinquan,
Zhang Lanjing,
Yang Wei,
Duan ShengZhong
Publication year - 2019
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5269
Subject(s) - angiogenesis , matrigel , stat3 , mineralocorticoid receptor , cancer research , biology , stat protein , endothelial stem cell , downregulation and upregulation , gene knockdown , microbiology and biotechnology , endocrinology , signal transduction , medicine , receptor , cell culture , biochemistry , genetics , gene , in vitro
The mineralocorticoid receptor (MR) plays important roles in cardiovascular pathogenesis. The function of MR in angiogenesis is still controversial. This study aimed to explore the role of endothelial MR in angiogenesis and to delineate the underlying mechanism. Endothelial‐hematopoietic MR knockout (EMRKO) mice were generated and subjected to hindlimb ischemia and injection of melanoma cells. Laser Doppler measurements showed that EMRKO mice had improved blood flow recovery and increased vessel density in ischemic limbs. In addition, EMRKO accelerated growth and increased the vessel density of tumors. Matrigel implantation, aortic ring assays, and tube formation assays demonstrated that MRKO endothelial cells (ECs) manifested increased angiogenic potential. MRKO ECs also displayed increased migration ability and proliferation. MRKO and MR knockdown both upregulated gene expression, protein level, and phosphorylation of signal transducer and activator of transcription 3 (STAT3). Stattic, a selective STAT3 inhibitor, attenuated the effects of MRKO on tube formation, migration, and proliferation of ECs. At the molecular level, MR interacted with CCAAT enhancer‐binding protein beta (C/EBPβ) to suppress the transcription of STAT3 . Furthermore, interactions between MR and STAT3 blocked the phosphorylation of STAT3. Finally, stattic abolished the pro‐angiogenic phenotype of EMRKO mice. Taken together, endothelial MR is a negative regulator of angiogenesis, likely in a ligand‐independent manner. Mechanistically, MR downregulates STAT3 that mediates the impacts of MR deficiency on the angiogenic activity of ECs and angiogenesis. Targeting endothelial MR may be a potential pro‐angiogenic strategy for ischemic diseases. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.