Role of early growth response 1 in arteriogenesis: Impact on vascular cell proliferation and leukocyte recruitment in vivo

Judith-Irina Pagel; Tibor Ziegelhoeffer; Matthias Heil; Silvia Fischer; Borja Fernández; Wolfgang Schaper; Klaus T. Preissner; Elisabeth Deindl

doi:10.1160/TH11-07-0490

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 107(03): 562-574
DOI: 10.1160/TH11-07-0490

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Role of early growth response 1 in arteriogenesis: Impact on vascular cell proliferation and leukocyte recruitment in vivo

Judith-Irina Pagel

¹Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany

,

Tibor Ziegelhoeffer

²Kerckhoff Clinic, Bad Nauheim, Germany

,

Matthias Heil

³Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

,

Silvia Fischer

⁴Department of Biochemistry, Justus-Liebig-University, Giessen, Germany

,

Borja Fernández

⁵Department of Animal Biology, Faculty of Science, University of Málaga, Málaga, Spain

,

Wolfgang Schaper

³Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

,

Klaus T. Preissner

⁴Department of Biochemistry, Justus-Liebig-University, Giessen, Germany

,

Elisabeth Deindl

¹Walter-Brendel-Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany

› Author Affiliations

Abstract

Summary

Based on previous findings that early growth response 1 (Egr-1) participates in leukocyte recruitment and cell proliferation in vitro, this study was designed to investigate its mode of action during arteriogenesis in vivo. In a model of peripheral arteriogenesis, Egr-1 was significantly upregulated in growing collaterals of wild-type (WT) mice, both on mRNA and protein level. Egr-1^−/− mice demonstrated delayed arteriogenesis after femoral artery ligation. They further showed increased levels of monocytes and granulocytes in the circulation, but reduced levels in adductor muscles under baseline conditions. After femoral artery ligation, elevated numbers of macrophages were detected in the perivascular zone of collaterals in Egr-1^−/− mice and mRNA of leukocyte recruitment mediators was upregulated. Other Egr family members (Egr-2 to -4) were significantly upregulated only in Egr-1^−/− mice, suggesting a mechanism of counterbalancing Egr-1 deficiency. Moreover, splicing factor-1, downregulated in WT mice after femoral artery ligation in the process of increased vascular cell proliferation, was upregulated in Egr-1^−/− mice. αSM-actin on the other hand, significantly downregulated in WT mice, showed no differential expression in Egr-1^−/− mice. While cell cycle regulator cyclin E and cdc20 were upregulated in Egr-1^−/− mice, cyclin D1 expression decreased below the detection limit in collaterals, and the proliferation marker ki67 was not differentially expressed. In conclusion, compensation for deficiency in Egr-1 function in leukocyte recruitment can presumably be mediated by other transcription factors; however, Egr-1 is indispensable for effective vascular cell cycle progression in arteriogenesis.

Keywords

Arteriogenesis - Egr-1 - SF-1 - vSMC phenotype switch

Full Text

References

References
1 Sukhatme VP, Kartha S, Toback FG. et al. A novel early growth response gene rapidly induced by fibroblast, epithelial cell and lymphocyte mitogens. Oncogene Res 1987; 01: 343-355.
2 Sukhatme VP, Cao XM, Chang LC. et al. A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization. Cell 1988; 53: 37-43.
3 Gashler A, Sukhatme VP. Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors. Prog Nucleic Acid Res Mol Biol 1995; 50: 191-224.
4 Cao XM, Koski RA, Gashler A. et al. Identification and characterization of the Egr-1 gene product, a DNA-binding zinc finger protein induced by differentiation and growth signals. Mol Cell Biol 1990; 10: 1931-1939.
5 Khachigian LM, Anderson KR, Halnon NJ. et al. Egr-1 is activated in endothelial cells exposed to fluid shear stress and interacts with a novel shear-stress-response element in the PDGF A-chain promoter. Arterioscler Thromb Vasc Biol 1997; 17: 2280-2286.
6 Nishi H, Nishi KH, Johnson AC. Early Growth Response-1 gene mediates upregulation of epidermal growth factor receptor expression during hypoxia. Cancer Res 2002; 62: 827-834.
7 Bonventre JV, Sukhatme VP, Bamberger M. et al. Localization of the protein product of the immediate early growth response gene, Egr-1, in the kidney after ischemia and reperfusion. Cell Regul 1991; 02: 251-260.
8 Brand T, Sharma HS, Fleischmann KE. et al. Proto-oncogene expression in porcine myocardium subjected to ischemia and reperfusion. Circ Res 1992; 71: 1351-1360.
9 Blaschke F, Bruemmer D, Law RE. Egr-1 is a major vascular pathogenic transcription factor in atherosclerosis and restenosis. Rev Endocr Metab Disord 2004; 05: 249-254.
10 Arai M, Uchiba M, Komura H. et al. Metformin, an antidiabetic agent, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro. J Pharmacol Exp Ther 2010; 334: 206-213.
11 Nozik-Grayck E, Suliman HB, Majka S. et al. Lung EC-SOD overexpression attenuates hypoxic induction of Egr-1 and chronic hypoxic pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 2008; 295: L422-430.
12 Sarateanu CS, Retuerto MA, Beckmann JT. et al. An Egr-1 master switch for arteriogenesis: studies in Egr-1 homozygous negative and wild-type animals. J Thorac Cardiovasc Surg 2006; 131: 138-145.
13 Lee YS, Jang HS, Kim JM. et al. Adenoviral-mediated delivery of early growth response factor-1 gene increases tissue perfusion in a murine model of hindlimb ischemia. Mol Ther 2005; 12: 328-336.
14 Deindl E, Schaper W. The art of arteriogenesis. Cell Biochem Biophys 2005; 43: 1-15.
15 Eitenmuller I, Volger O, Kluge A. et al. The range of adaptation by collateral vessels after femoral artery occlusion. Circ Res 2006; 99: 656-662.
16 Arras M, Ito WD, Scholz D. et al. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 1998; 101: 40-50.
17 Deindl E, Hoefer IE, Fernandez B. et al. Involvement of the fibroblast growth factor system in adaptive and chemokine-induced arteriogenesis. Circ Res 2003; 92: 561-568.
18 Voskuil M, Hoefer IE, van Royen N. et al. Abnormal monocyte recruitment and collateral artery formation in monocyte chemoattractant protein-1 deficient mice. Vasc Med 2004; 09: 287-292.
19 Hoefer IE, van Royen N, Rectenwald JE. et al. Arteriogenesis proceeds via ICAM-1/Mac-1– mediated mechanisms. Circ Res 2004; 94: 1179-1185.
20 Gyetko MR, Todd 3rd RF, Wilkinson CC. et al. The urokinase receptor is required for human monocyte chemotaxis in vitro. J Clin Invest 1994; 93: 1380-1387.
21 Scholz D, Ito W, Fleming I. et al. Ultrastructure and molecular histology of rabbit hind-limb collateral artery growth (arteriogenesis). Virchows Arch 2000; 436: 257-270.
22 Deindl E, Ziegelhoffer T, Kanse SM. et al. Receptor-independent role of the urokinase-type plasminogen activator during arteriogenesis. FASEB J 2003; 17: 1174-1176.
23 Demicheva E, Hecker M, Korff T. Stretch-induced activation of the transcription factor activator protein-1 controls monocyte chemoattractant protein-1 expression during arteriogenesis. Circ Res 2008; 103: 477-484.
24 Bain G, Cravatt CB, Loomans C. et al. Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade. Nat Immunol 2001; 02: 165-171.
25 Yan SF, Fujita T, Lu J. et al. Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress. Nat Med 2000; 06: 1355-1361.
26 Kharbanda S, Nakamura T, Stone R. et al. Expression of the early growth response 1 and 2 zinc finger genes during induction of monocytic differentiation. J Clin Invest 1991; 88: 571-577.
27 Nguyen HQ, Hoffman-Liebermann B, Liebermann DA. The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage. Cell 1993; 72: 197-209.
28 Liao Y, Shikapwashya ON, Shteyer E. et al. Delayed hepatocellular mitotic progression and impaired liver regeneration in early growth response-1-deficient mice. J Biol Chem 2004; 279: 43107-43116.
29 Xiao D, Chinnappan D, Pestell R. et al. Bombesin regulates cyclin D1 expression through the early growth response protein Egr-1 in prostate cancer cells. Cancer Res 2005; 65: 9934-9942.
30 Cattaruzza M, Schafer K, Hecker M. Cytokine-induced downregulation of zfm1/splicing factor-1 promotes smooth muscle cell proliferation. J Biol Chem 2002; 277: 6582-6589.
31 Limbourg A, Korff T, Napp LC. et al. Evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia. Nat Protoc 2009; 04: 1737-1746.
32 Scholz D, Ziegelhoeffer T, Helisch A. et al. Contribution of arteriogenesis and angiogenesis to postocclusive hindlimb perfusion in mice. J Mol Cell Cardiol 2002; 34: 775-787.
33 Kanse SM, Benakour O, Kanthou C. et al. Induction of vascular SMC proliferation by urokinase indicates a novel mechanism of action in vasoproliferative disorders. Arterioscler Thromb Vasc Biol 1997; 17: 2848-2854.
34 Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-159.
35 Deindl E, Boengler K, van Royen N. et al. Differential expression of GAPDH and beta3-actin in growing collateral arteries. Mol Cell Biochem 2002; 236: 139-146.
36 Barancik M, Htun P, Strohm C. et al. Inhibition of the cardiac p38-MAPK pathway by SB203580 delays ischemic cell death. J Cardiovasc Pharmacol 2000; 35: 474-483.
37 Wolf C, Cai WJ, Vosschulte R. et al. Vascular remodeling and altered protein expression during growth of coronary collateral arteries. J Mol Cell Cardiol 1998; 30: 2291-2305.
38 Cai WJ, Kocsis E, Wu X. et al. Remodeling of the vascular tunica media is essential for development of collateral vessels in the canine heart. Mol Cell Biochem 2004; 264: 201-210.
39 Bergmann CE, Hoefer IE, Meder B. et al. Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice. J Leukoc Biol 2006; 80: 59-65.
40 Cullen EM, Brazil JC, O'Connor CM. Mature human neutrophils constitutively express the transcription factor EGR-1. Mol Immunol 2010; 47: 1701-1709.
40 Schmidt J, Stoffels B, Moore BA. Proinflammatory role of leukocyte-derived Egr-1 in the development of murine postoperative ileus. Gastroenterology. 2008 135. 926-36. 36 e1-2
41 Krishnaraju K, Hoffman B, Liebermann DA. Early growth response gene 1 stimulates development of hematopoietic progenitor cells along the macrophage lineage at the expense of the granulocyte and erythroid lineages. Blood 2001; 97: 1298-1305.
42 Krishnaraju K, Nguyen HQ, Liebermann DA. et al. The zinc finger transcription factor Egr-1 potentiates macrophage differentiation of hematopoietic cells. Mol Cell Biol 1995; 15: 5499-5507.
43 Joseph LJ, Le Beau MM, Jamieson Jr GA. et al. Molecular cloning, sequencing, and mapping of EGR2, a human early growth response gene encoding a protein with “zinc-binding finger” structure. Proc Natl Acad Sci USA 1988; 85: 7164-7168.
44 Patwardhan S, Gashler A, Siegel MG. et al. EGR3, a novel member of the Egr family of genes encoding immediate-early transcription factors. Oncogene 1991; 06: 917-928.
45 Crosby SD, Puetz JJ, Simburger KS. et al. The early response gene NGFI-C encodes a zinc finger transcriptional activator and is a member of the GCGGGGGCG (GSG) element-binding protein family. Mol Cell Biol 1991; 11: 3835-3841.
46 Collins S, Lutz MA, Zarek PE. et al. Opposing regulation of T cell function by Egr-1/NAB2 and Egr-2/Egr-3. Eur J Immunol 2008; 38: 528-536.
47 Lee SL, Wang Y, Milbrandt J. Unimpaired macrophage differentiation and activation in mice lacking the zinc finger transplantation factor NGFI-A (EGR1). Mol Cell Biol 1996; 16: 4566-4572.
48 Wieland GD, Nehmann N, Muller D. et al. Early growth response proteins EGR-4 and EGR-3 interact with immune inflammatory mediators NF-kappaB p50 and p65. J Cell Sci 2005; 118: 3203-3212.
49 Gururajan M, Simmons A, Dasu T. et al. Early growth response genes regulate B cell development, proliferation, and immune response. J Immunol 2008; 181: 4590-4602.
50 Lee SL, Tourtellotte LC, Wesselschmidt RL. et al. Growth and differentiation proceeds normally in cells deficient in the immediate early gene NGFI-A. J Biol Chem 1995; 270: 9971-9977.
51 Boengler K, Pipp F, Broich K. et al. Identification of differentially expressed genes like cofilin2 in growing collateral arteries. Biochem Biophys Res Commun 2003; 300: 751-756.
52 Cai WJ, Kocsis E, Scholz D. et al. Presence of Cx37 and lack of desmin in smooth muscle cells are early markers for arteriogenesis. Mol Cell Biochem 2004; 262: 17-23.