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J Pathol. 2019 Aug;248(4):438-451. doi: 10.1002/path.5269. Epub 2019 May 6.

Mineralocorticoid receptor negatively regulates angiogenesis through repression of STAT3 activity in endothelial cells.

Zheng XJ1,2, Liu Y2, Zhang WC1, Liu Y1, Li C3, Sun XN1,2, Zhang YY1,2, Xu J4, Jiang X5, Zhang L6,7,8,9, Yang W10, Duan SZ1,2.

Author information

1
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, PR China.
2
Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China.
3
Division of Cardiology, Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, TX, USA.
4
Department of Infectious Disease, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
5
Department of Prosthodontics, Shanghai Ninth People's Hospital, School of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, PR China.
6
Department of Pathology, Princeton Medical Center, Plainsboro, NJ, USA.
7
Department of Biological Science, Rutgers University, Newark, NJ, USA.
8
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
9
Cancer Institute of New Jersey, Rutgers University, Piscataway, NJ, USA.
10
Department of Pathology, School of Basic Medical Sciences & Nanfang Hospital, Southern Medical University, Guangzhou, PR China.

Abstract

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.

KEYWORDS:

STAT3; angiogenesis; endothelial cells; mineralocorticoid receptor

PMID:
30900255
DOI:
10.1002/path.5269

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