miR‑376b‑5p regulates angiogenesis in cerebral ischemia

Li,Ling‑Juan; Huang,Qing; Zhang,Ning; Wang,Gui-Bin; Liu,Yun‑Hai

doi:10.3892/mmr.2014.2172

July-2014 Volume 10 Issue 1

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

July-2014 Volume 10 Issue 1

Full Size Image

Article

miR‑376b‑5p regulates angiogenesis in cerebral ischemia

Authors:
- Ling‑Juan Li
- Qing Huang
- Ning Zhang
- Gui-Bin Wang
- Yun‑Hai Liu
View Affiliations / Copyright

Affiliations: Department of Neurology, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
Pages: 527-535
|
Published online on: April 24, 2014

https://doi.org/10.3892/mmr.2014.2172
Expand metrics +

Abstract

The profile of microRNAs (miRNAs) altered following middle cerebral artery occlusion (MCAO) and miRNAs are involved in angiogenesis following cerebral ischemia. miR‑376b‑5p was decreased following MCAO, however, whether miR‑376b‑5p is important in angiogenesis remains to be elucidated. The present study was designed to identify whether miR‑376b‑5p is involved in angiogenesis following cerebral ischemia and to elucidate the underlying mechanisms. A rat MCAO model was established and quantitative polymerase chain reaction was performed to analyze the mRNA expression level of miR‑376b‑5p for 1 to 7 days. In addition, the density of microvessels and the relative mRNA and protein levels of hypoxia‑inducible factor‑1 α (HIF‑1α), vascular endothelial growth factor A (VEGFA) and Notch1 were measured. The miR‑376b‑5p mimic or the miR‑376b‑5p inhibitor were transfected into hypoxic human umbilical vein endothelial cells (HUVECs), and the proliferation, migration and tube formation were measured. To further examine the underlying mechanisms, shRNA was transfected into cells to knock down HIF‑1α, and angiogenesis and the expression of associated molecules, including HIF‑1α, VEGFA and Notch1 were compared between each group. Our results demonstrated that miR‑376b‑5p repressed angiogenesis in vivo and in vitro, and miR‑376b‑5p inhibited angiogenesis in HUVECs by targeting the HIF‑1α‑mediated VEGFA/Notch1 signaling pathway. These findings provide new insights into angiogenesis therapy for cerebral ischemia.

View Figures

View References

1	Wang WZ: Neurology. 4th edition. People’s Medical Publishing House; Beijing: pp. 1302001
2	Zhu XF, Rao ML, Peng J, et al: Dynamis observed morphologic change of neuron and microcirculation in focal cerebral ischemia and reperfusion of rat. Chin J Clin Rehabil. 6:1904–1905. 2002.
3	Bang OY, Saver JL, Buck BH, et al; UCLA Collateral Investigators. Impact of collateral flow on tissue fate in acute ischaemic stroke. J Neurol Neurosurg Psychiatry. 79:625–629. 2008. View Article : Google Scholar : PubMed/NCBI
4	Liebeskind DS, Cotsonis GA, Saver JL, et al; Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) Investigators. Collaterals dramatically alter stroke risk in intracranial atherosclerosis. Ann Neurol. 69:963–974. 2011. View Article : Google Scholar : PubMed/NCBI
5	Miteff F, Levi CR, Bateman GA, et al: The independent predictive utility of computed tomography angiographic collateral status in acute ischaemic stroke. Brain. 132:2231–2238. 2009. View Article : Google Scholar : PubMed/NCBI
6	Krupinski J, Kaluza J, Kumar P, et al: Role of angiogenesis in patients with cerebral ischemic stroke. Stroke. 25:1794–1798. 1994. View Article : Google Scholar : PubMed/NCBI
7	Wu F, Yang Z and Li G: Role of specific microRNAs for endothelial function and angiogenesis. Biochem Biophys Res Commun. 386:549–553. 2009. View Article : Google Scholar : PubMed/NCBI
8	Longa EZ, Weinstein PR, Carlson S, et al: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 20:84–91. 1989. View Article : Google Scholar
9	Fire A, Xu S, Montgomery MK, et al: Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 391:806–811. 1998. View Article : Google Scholar : PubMed/NCBI
10	Caplen NJ, Parrish S, Imani F, et al: Specific inhibition of gene expression by small doublestranded RNAs in invertebrate and vertebrate systems. Proc Natl Acad Sci USA. 98:9742–9747. 2001. View Article : Google Scholar : PubMed/NCBI
11	Grishok A, Pasquinelli AE, Conte D, et al: Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell. 106:23–34. 2001. View Article : Google Scholar : PubMed/NCBI
12	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
13	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
14	Humphreys DT, Westman BJ, Martin DI, et al: MicroRNAs control translation initiation by inhibiting eukaryotic initiation factor 4E/cap and poly(A) tail function. Proc Natl Acad Sci USA. 102:16961–16966. 2005. View Article : Google Scholar : PubMed/NCBI
15	Jing Q, Huang S, Guth S, et al: Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell. 120:623–634. 2005. View Article : Google Scholar : PubMed/NCBI
16	Kulshreshtha R, Ferracin M, Wojcik SE, et al: A microRNA signature of hypoxia. Mol Cell Biol. 27:1859–1867. 2007. View Article : Google Scholar
17	Wen QQ, Jia YJ, Wang MC, et al: Expression analysis of microRNA on acute cerebral ischemia in rats. J Chongqing Univ. 33:23–26. 2005.
18	Roy S, Khanna S, Hussain SR, et al: MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue. Cardiovasc Res. 82:21–29. 2009. View Article : Google Scholar : PubMed/NCBI
19	Shen J, Yang X, Xie B, et al: MicroRNAs regulate ocular neovascularization. Mol Ther. 16:1208–1216. 2008. View Article : Google Scholar : PubMed/NCBI
20	Dharap A, Bowen K, Place R, et al: Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab. 29:675–687. 2009. View Article : Google Scholar : PubMed/NCBI
21	Velazquez OC, Snyder R, Liu ZJ, et al: Fibroblast-dependent differentiation of human microvaseular endothelial cells into capillary-like 3-dimensional networks. FASEB J. 16:1316–1318. 2002.PubMed/NCBI
22	Beck H and Plate KH: Angiogenesis after cerebral ischemia. Acta Neuropathol. 117:481–496. 2009. View Article : Google Scholar
23	Guo X, Liu L, Zhang M, et al: Correlation of CD34⁺ cells with tissue angiogenesis after traumatic brain injury in a rat model. J Neurotrauma. 26:1337–1344. 2009.
24	Yancopoulos GD: Vascular-specific growth factors and blood vessel formation. Nature. 407:242–248. 2000. View Article : Google Scholar : PubMed/NCBI
25	Zhang ZG, Zhang L, Jiang Q, et al: VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest. 106:829–838. 2000. View Article : Google Scholar : PubMed/NCBI
26	Risau W: Mechanisms of angiogenesis. Nature. 386:671–674. 1997. View Article : Google Scholar : PubMed/NCBI
27	Abumiya T, Lucero J, Heo JH, et al: Activated microvessels express vascular endothelial growth factor and integrin alpha(v)beta3 during focal cerebral ischemia. J Cereb Blood Flow Metab. 19:1038–1050. 1999. View Article : Google Scholar
28	Sondell M, Lundborg G and Kanje M: Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system. J Neurosci. 19:5731–5740. 1999.
29	Schratzberger P, Schratzberger G, Silver M, et al: Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy. Nat Med. 6:405–413. 2000. View Article : Google Scholar : PubMed/NCBI
30	Zhang ZJ and He L: Vascular endothelial growth factor and ischemic cerebrovascular disease. Chin J Clin Rehabil. 8:131972004.
31	Greenberg DA and Jin K: From angiogenesis to neuropathology. Nature. 438:954–959. 2005. View Article : Google Scholar : PubMed/NCBI
32	Limbourg FP, Takeshita K, Radtke F, et al: Essential role of endothelial Notch1 in angiogenesis. Circulation. 111:1826–1832. 2005. View Article : Google Scholar : PubMed/NCBI
33	Song Cai-Li, Zhang Feng-Chun, Xu Ying-Chun, et al: Effect of breast cancer stromal cells on expression of Wntl, Notchl and β-catenin and migration of MCF-7 cells. Medical Bulletin of Shanghai Jiaotong University. 28:921–924. 2008.
34	Hainaud P, Contrerès JO, Villemain A, et al: The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer Res. 66:8501–8510. 2006. View Article : Google Scholar : PubMed/NCBI
35	Jin KL, Mao XO, Nagayama T, et al: Induction of vascular endothelial growth factor and hypoxia-inducible factor-1alpHa by global ischemia in rat brain. Neuroscience. 99:577–585. 2000. View Article : Google Scholar : PubMed/NCBI
36	Sharp FR, Lu A, Tang Y, et al: Multiple molecular penumbras after focal cerebral ischemia. J Cereb Blood Flow Metab. 20:1011–1032. 2000. View Article : Google Scholar : PubMed/NCBI
37	Carmeliet P: Mechanisms of angiogenesis and arteriogenesis. Nat Med. 6:389–395. 2000. View Article : Google Scholar : PubMed/NCBI
38	Bonauer A, Carmona G, Iwasaki M, et al: MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 324:1710–1713. 2009. View Article : Google Scholar : PubMed/NCBI
39	Jeyaseelan K, Lim KY and Armugam A: MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke. 39:959–966. 2008. View Article : Google Scholar : PubMed/NCBI
40	Taguchi A, Yanagisawa K, Tanaka M, et al: Identification of hypoxia-inducible factor-1 alpha as a novel target for miR-17–92 microRNA cluster. Cancer Res. 68:5540–5545. 2008.PubMed/NCBI
41	Ghosh G, Subramanian IV, Adhikari N, et al: Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Invest. 120:4141–4154. 2010. View Article : Google Scholar : PubMed/NCBI
42	Cascio S, D’Andrea A, Ferla R, et al: miR-20b modulates VEGF expression by targeting HIF-1 alpha and STAT3 in MCF-7 breast cancer cells. J Cell Physiol. 224:242–249. 2010.PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

miR‑376b‑5p regulates angiogenesis in cerebral ischemia

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Related Articles