LIM Domain Only 2 Regulates Endothelial Proliferation, Angiogenesis, and Tissue Regeneration

Overview

Journal J Am Heart Assoc

Specialty Cardiology & Vascular Diseases

Date 2016 Oct 30

PMID 27792641

Citations 14

Authors

Shu Meng

Gianfranco Matrone

Jie Lv

Kaifu Chen

Wing Tak Wong

John P Cooke

Affiliations

Soon will be listed here.

Abstract

Background: LIM domain only 2 (LMO2, human gene) is a key transcription factor that regulates hematopoiesis and vascular development. However, its role in adult endothelial function has been incompletely characterized.

Methods And Results: In vitro loss- and gain-of-function studies on LMO2 were performed in human umbilical vein endothelial cells with lentiviral overexpression or short hairpin RNA knockdown (KD) of LMO2, respectively. LMO2 KD significantly impaired endothelial proliferation. LMO2 controls endothelial G1/S transition through transcriptional regulation of cyclin-dependent kinase 2 and 4 as determined by reverse transcription polymerase chain reaction (PCR), western blot, and chromatin immunoprecipitation, and also influences the expression of Cyclin D1 and Cyclin A1. LMO2 KD also impaired angiogenesis by reducing transforming growth factor-β (TGF-β) expression, whereas supplementation of exogenous TGF-β restored defective network formation in LMO2 KD human umbilical vein endothelial cells. In a zebrafish model of caudal fin regeneration, RT-PCR revealed that the lmo2 (zebrafish gene) gene was upregulated at day 5 postresection. The KD of lmo2 by vivo-morpholino injections in adult Tg(fli1:egfp) zebrafish reduced 5-bromo-2'-deoxyuridine incorporation in endothelial cells, impaired neoangiogenesis in the resected caudal fin, and substantially delayed fin regeneration.

Conclusions: The transcriptional factor LMO2 regulates endothelial proliferation and angiogenesis in vitro. Furthermore, LMO2 is required for angiogenesis and tissue healing in vivo. Thus, LMO2 is a critical determinant of vascular and tissue regeneration.

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References

Coma S, Allard-Ratick M, Akino T, van Meeteren L, Mammoto A, Klagsbrun M . GATA2 and Lmo2 control angiogenesis and lymphangiogenesis via direct transcriptional regulation of neuropilin-2. Angiogenesis. 2013; 16(4):939-52. PMC: 3793839. DOI: 10.1007/s10456-013-9370-9. View

Neale G, Rehg J, Goorha R . Disruption of T-cell differentiation precedes T-cell tumor formation in LMO-2 (rhombotin-2) transgenic mice. Leukemia. 1997; 11 Suppl 3:289-90. View

Pugach E, Li P, White R, Zon L . Retro-orbital injection in adult zebrafish. J Vis Exp. 2009; (34). PMC: 3149973. DOI: 10.3791/1645. View

Yamada Y, Pannell R, Forster A, Rabbitts T . The oncogenic LIM-only transcription factor Lmo2 regulates angiogenesis but not vasculogenesis in mice. Proc Natl Acad Sci U S A. 2000; 97(1):320-4. PMC: 26661. DOI: 10.1073/pnas.97.1.320. View

Gratzinger D, Zhao S, West R, Rouse R, Vogel H, Gil E . The transcription factor LMO2 is a robust marker of vascular endothelium and vascular neoplasms and selected other entities. Am J Clin Pathol. 2009; 131(2):264-78. PMC: 4305438. DOI: 10.1309/AJCP5FP3NAXAXRJE. View

Foubert P, Matrone G, Souttou B, Lere-Dean C, Barateau V, Plouet J . Coadministration of endothelial and smooth muscle progenitor cells enhances the efficiency of proangiogenic cell-based therapy. Circ Res. 2008; 103(7):751-60. DOI: 10.1161/CIRCRESAHA.108.175083. View

Pepper M . Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev. 1997; 8(1):21-43. DOI: 10.1016/s1359-6101(96)00048-2. View

Appert A, Nam C, Lobato N, Priego E, Miguel R, Blundell T . Targeting LMO2 with a peptide aptamer establishes a necessary function in overt T-cell neoplasia. Cancer Res. 2009; 69(11):4784-90. PMC: 2690635. DOI: 10.1158/0008-5472.CAN-08-4774. View

Bianconi E, Piovesan A, Facchin F, Beraudi A, Casadei R, Frabetti F . An estimation of the number of cells in the human body. Ann Hum Biol. 2013; 40(6):463-71. DOI: 10.3109/03014460.2013.807878. View

10.

Goode D, Obier N, Vijayabaskar M, Lie-A-Ling M, Lilly A, Hannah R . Dynamic Gene Regulatory Networks Drive Hematopoietic Specification and Differentiation. Dev Cell. 2016; 36(5):572-87. PMC: 4780867. DOI: 10.1016/j.devcel.2016.01.024. View

11.

Lee S, Choi Y, Cha J, Moon E, Lee S, Bae M . Identification of novel anti-angiogenic factors by in silico functional gene screening method. J Biotechnol. 2003; 105(1-2):51-60. DOI: 10.1016/s0168-1656(03)00183-4. View

12.

Cleveland S, Smith S, Tripathi R, Mathias E, Goodings C, Elliott N . Lmo2 induces hematopoietic stem cell-like features in T-cell progenitor cells prior to leukemia. Stem Cells. 2013; 31(5):882-94. PMC: 3652616. DOI: 10.1002/stem.1345. View

13.

Schmeichel K, Beckerle M . The LIM domain is a modular protein-binding interface. Cell. 1994; 79(2):211-9. DOI: 10.1016/0092-8674(94)90191-0. View

14.

Boehm T, Foroni L, Kaneko Y, Perutz M, Rabbitts T . The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. Proc Natl Acad Sci U S A. 1991; 88(10):4367-71. PMC: 51660. DOI: 10.1073/pnas.88.10.4367. View

15.

Xu C, Hasan S, Schmidt I, Rocha S, Pitulescu M, Bussmann J . Arteries are formed by vein-derived endothelial tip cells. Nat Commun. 2014; 5:5758. PMC: 4275597. DOI: 10.1038/ncomms6758. View

16.

Patterson L, Gering M, Patient R . Scl is required for dorsal aorta as well as blood formation in zebrafish embryos. Blood. 2005; 105(9):3502-11. DOI: 10.1182/blood-2004-09-3547. View

17.

Poss K, Shen J, Nechiporuk A, McMahon G, Thisse B, Thisse C . Roles for Fgf signaling during zebrafish fin regeneration. Dev Biol. 2000; 222(2):347-58. DOI: 10.1006/dbio.2000.9722. View

18.

Sun Z, Cai Y, Chen G, Wang R, Jia J, Chen X . LMO2 promotes angiogenesis probably by up-regulation of bFGF in endothelial cells: an implication of its pathophysiological role in infantile haemangioma. Histopathology. 2010; 57(4):622-32. DOI: 10.1111/j.1365-2559.2010.03676.x. View

19.

Yamada Y, Pannell R, Forster A, Rabbitts T . The LIM-domain protein Lmo2 is a key regulator of tumour angiogenesis: a new anti-angiogenesis drug target. Oncogene. 2002; 21(9):1309-15. DOI: 10.1038/sj.onc.1205285. View

20.

von Tell D, Armulik A, Betsholtz C . Pericytes and vascular stability. Exp Cell Res. 2005; 312(5):623-9. DOI: 10.1016/j.yexcr.2005.10.019. View