Skip to main content

Advertisement

Log in

Leptin and vascular endothelial growth factor regulate angiogenesis in tooth germs

  • Original Paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Leptin, a 16 kDa non-glycolated polypeptide of 146 amino acids produced by the ob gene, has a variety of physiological roles not only in lipid metabolism, hematopoiesis, thermogenesis and ovarian function, but also in angiogenesis. This study focuses to investigate the possibility that leptin, as an angiogenic factor, may regulate the angiogenesis during tooth development. We firstly studied the expression of leptin and vascular endothelial growth factor (VEGF) during tooth development immunohistochemically. This investigation revealed that leptin is expressed in ameloblasts, odontoblasts, dental papilla cells and stratum intermedium cells. This expression pattern was similar to that of VEGF, one of the most potent angiogenic factors. Interestingly, more leptin-positive cells were observed in the upper third portion of dental papilla, which is closest to odontoblastic layer, compared to middle and lower thirds. Moreover, in the dental papilla, more CD31 and/or CD34-positive vascular endothelial cells were observed in the vicinity of ameloblasts and odontoblasts expressing leptin and VEGF. These findings strongly suggest that ameloblasts, odontoblasts and dental papilla cells induce the angiogenesis in tooth germs by secretion of leptin as well as VEGF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Aida M, Irié T, Aida T, Tachikawa T (2005) Expression of protein kinases C βI, βII, and VEGF during the differentiation of enamel epithelium in tooth development. J Dent Res 84:234–239

    Article  PubMed  CAS  Google Scholar 

  • Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, Moizo L, Lehy T, Guerre-Millo M, Marchand-Brustel YL, Lewin MJM (1998) The stomach is a source of leptin. Nature 394:790–793

    Article  PubMed  CAS  Google Scholar 

  • Bouloumie A, Drexler HCA, Lafontan M, Busse R (1998) Leptin, the product of ob gene, promotes angiogenesis. Circ Res 83:1059–1066

    PubMed  CAS  Google Scholar 

  • Brown LF, Yeo KT, Berse B, Yeo TK, Senger DR, Dvorak HF, van de Water L (1992) Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med 176:1375–1379

    Article  PubMed  CAS  Google Scholar 

  • Bryson JM, Phuyal JL, Swan V, Caterson ID (1999) Leptin has acute effects on glucose and lipid metabolism in both lean and gold thioglucose-obese mice. Am J Physiol 277:E417–E422

    PubMed  CAS  Google Scholar 

  • DeLisser HM, Newman PJ, Albelda SM (1994) Molecular and functional aspects of PECAM-1/CD31. Immunol Today 15:490–495

    Article  PubMed  CAS  Google Scholar 

  • DeYoung BR, Swanson PE, Argenyi ZB, Ritter JH, Fitzgibbon JF, Stahl DJ, Hoover W, Wick MR (1995) CD31 immunoreactivity in mesenchymal neoplasms of the skin and subcutis: report of 145 cases and review of putative immunohistologic markers of endothelial differentiation. J Cutan Pathol 22:215–222

    Article  PubMed  CAS  Google Scholar 

  • Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100:197–207

    Article  PubMed  CAS  Google Scholar 

  • Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

    Article  PubMed  CAS  Google Scholar 

  • Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770

    Article  PubMed  CAS  Google Scholar 

  • Gainsford T, Willson TA, Metcalf D, Handman E, McFarlane C, Ng A, Nicola NA, Alexander WS, Hilton DJ (1996) Leptin can induce proliferation, differentiation, and functional activation of hematopoietic cells. Proc Natl Acad Sci USA 93:14564–14568

    Article  PubMed  CAS  Google Scholar 

  • Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N (1999) VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 6:623–6288

    Google Scholar 

  • Gilbert SF (2000) Developmental biology, 6th edn. Sinauer Associates, Sunderland, pp 420–422

    Google Scholar 

  • Griga T, Tromm A, Spranger J, May B (1998) Increased serum levels of vascular endothelial growth factor in patients with inflammatory bowel disease. Scand J Gastroenterol 33:504–508

    Article  PubMed  CAS  Google Scholar 

  • Harada M, Mitsuyama K, Yoshida H, Sakisaka S, Taniguchi E, Kawaguchi T, Ariyoshi M, Saiki T, Sakamoto M, Nagata K, Sata M, Matsuo K, Tanikawa K (1998) Vascular endothelial growth factor in patients with rheumatoid arthritis. Scand J Rheumatol 27:377–380

    Article  PubMed  CAS  Google Scholar 

  • Hoggard N, Hunter L, Trayhurn P, Williams LM, Mercer JG (1998) Leptin and reproduction. Proc Nutr Soc 1998(57):421–427

    Article  Google Scholar 

  • Hwa JJ, Ghibaudi L, Compton D, Fawzi AB, Strader CD (1996) Intracerebroventricular injection of leptin increases thermogenesis and mobilizes fat metabolism in ob/ob mice. Horm Metab Res 8:659–663

    Article  Google Scholar 

  • Jernvall J, Thesleff I (2000) Reiterative signaling and patterning in mammalian tooth morphogenesis. Mech Dev 92:19–29

    Article  PubMed  CAS  Google Scholar 

  • Jin L, Burguera BG, Couce ME, Scheithauer BW, Lamsan J, Eberhardt NL, Kulig E, Lloyd RV (1999) Leptin and leptin receptor expression in normal and neoplastic human pituitary: evidence of a regulatory role for leptin on pituitary cell proliferation. J Clin Endocrinol Metab 84:2903–2911

    Article  PubMed  CAS  Google Scholar 

  • Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844

    Article  PubMed  CAS  Google Scholar 

  • Kumasaka S, Shimozuma M, Kawamoto T, Mishima K, Tokuyama R, Kamiya Y, Davaadorj P, Saito I, Satomura K (2010) Possible involvement of melatonin in tooth development: expression of melatonin 1a receptor in human and mouse tooth germs. Histochem Cell Biol 133:577–584

    Article  PubMed  CAS  Google Scholar 

  • Kume K, Satomura K, Nishisho S, Kitaoka E, Yamanouchi K, Tobiume S, Nagayama M (2002) Potential role of leptin in endochondral ossification. J Histochem Cytochem 50:159–169

    PubMed  CAS  Google Scholar 

  • Lumsden A (1988) Spatial organization of the epithelium and the role of neural crest cell in the initiation of the mammalian tooth germ. Development 103:155–169

    PubMed  Google Scholar 

  • Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K (1997) Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 3:1029–1033

    Article  PubMed  CAS  Google Scholar 

  • Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367:576–579

    Article  PubMed  CAS  Google Scholar 

  • Miwa Y, Fujita T, Sunohara M, Sato I (2008) Immunocytochemical localization of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 of the human deciduous molar tooth germ development in the human fetus. Ann Anat 190:246–251

    Article  PubMed  Google Scholar 

  • Morash B, Li A, Murphy PR, Wilkinson M, Ur E (1999) Leptin gene expression in the brain and pituitary gland. Endocrinology 140:5995–5998

    Article  PubMed  CAS  Google Scholar 

  • Nait Lechguer A, Kuchler-Bopp S, Hu B, Haïkel Y, Lesot H (2008) Vascularization of engineered teeth. J Dent Res 12:1138–1143

    Google Scholar 

  • Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 13:9–22

    PubMed  CAS  Google Scholar 

  • Newman PJ, Berndt MC, Gorski J, White GC 2nd, Lyman S, Paddock C, Muller WA (1990) PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 247:1219–1222

    Article  PubMed  CAS  Google Scholar 

  • Norrby K (1998) Microvascular density in terms of number and length of microvessel segments per unit tissue volume in mammalian angiogenesis. Microvasc Res 55:43–53

    Article  PubMed  CAS  Google Scholar 

  • Parums DV, Cordell JL, Micklem K, Heryet AR, Gatter KC, Mason DY (1990) JC70: a new monoclonal antibody that detects vascular endothelium associated antigen on routinely processed tissue sections. J Clin Pathol 43:752–757

    Article  PubMed  CAS  Google Scholar 

  • Reseland JE, Syversen U, Bakke I, Qvigstad G, Eide LG, Hjertner Ø, Gordeladze JO, Drevon CA (2001) Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralization. J Bone Miner Res 16:1426–1433

    Article  PubMed  CAS  Google Scholar 

  • Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapetropoulos A, Sessa WC, Madge LA, Schechner JS, Schwabb MB, Polverini PJ, Flores-Riveros JR (1998) Biological action of leptin as an angiogenic factor. Science 281:1683–1686

    Article  PubMed  CAS  Google Scholar 

  • Spector JA, Mehrara BJ, Greenwald JA, Saadeh PB, Steinbrech DS, Bouletreau PJ, Smith LP, Longaker MT (2000) Osteoblast expression of vasucular endothelial growth factor is modulated by the extracellular microenvironment. Am J Physiol Cell Physiol 280:C72–C80

    Google Scholar 

  • Spicer LJ, Francisco CC (1997) The adipose obese gene product, leptin evidence of a direct inhibitory role in ovarian function. Endocrinology 138:3374–3379

    Article  PubMed  CAS  Google Scholar 

  • Talavera-Adame D, Xiong Y, Zhao T, Arias AE, Sierra-Honigmann MR, Farkas DL (2008) Quantitative and morphometric evaluation of the angiogenic effects of leptin. J Biomed Opt 13:064017

    Article  PubMed  Google Scholar 

  • Ten Cate AR (1994) Oral histology, 4th edn. Mosby, St. Louis, pp 58–80

    Google Scholar 

  • Thesleff I, Mikkola M (2002) The role of growth factors in tooth development. Int Rev Cytol 217:93–135

    Article  PubMed  CAS  Google Scholar 

  • Thesleff I, Partanen AM, Vainio S (1991) Epithelial–mesenchymal interactions in tooth morphogenesis: the roles of extracellular matrix, growth factors, and cell surface receptors. J Craniofac Genet Dev Biol 11:229–237

    PubMed  CAS  Google Scholar 

  • Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L (1998) A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 393:684–688

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research (21592575, 22791986 and 22592233) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kazuhito Satomura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ide, S., Tokuyama, R., Davaadorj, P. et al. Leptin and vascular endothelial growth factor regulate angiogenesis in tooth germs. Histochem Cell Biol 135, 281–292 (2011). https://doi.org/10.1007/s00418-011-0789-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-011-0789-z

Keywords

Navigation