© 1998 American Heart Association, Inc.
Rapid Communication |
Leptin, the Product of Ob Gene, Promotes Angiogenesis
From Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität (A.B., R.B.), Frankfurt/Main, Germany; Max-Planck-Institut für physiologische und klinische Forschung (H.C.A.D.), Bad Nauheim, Germany; and INSERM U317, Institut Louis Bugnard, CHU Rangueil (M.L.), Toulouse, France.
Correspondence to Dr Anne Bouloumié, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany. E-mail bouloumie{at}em.uni-frankfurt.de
Abstract
Abstract—The adipocyte-derived cytokine leptin is thought to play a key role in the control of satiety and energy expenditure. Because adipogenesis and angiogenesis are tightly correlated during the fat mass development, we tested the hypothesis that leptin is able to modulate the growth of the vasculature. Experiments were performed using cultured human umbilical venous endothelial cells (HUVECs) and porcine aortic endothelial cells. The presence of 170-kDa endothelial leptin receptor (Ob-R) was assessed in HUVECs by Western blot analysis. Reverse transcriptase–polymerase chain reaction analysis using specific oligonucleotides for the short and long Ob-R forms further revealed the expression of both Ob-R transcripts in endothelial cells. Moreover, leptin evoked a time-dependent tyrosine phosphorylation of a number of endothelial proteins, the most prominent of which were the mitogen-activated protein kinases Erk1/2. Treatment of HUVECs with leptin led to a concentration-dependent increase in cell number that was maximal at 10 ng/mL leptin and equivalent to that elicited by vascular endothelial growth factor. This effect was associated with an enhanced formation of capillary-like tubes in an in vitro angiogenesis assay and neovascularization in an in vivo model of angiogenesis. These results indicate that leptin, via activation of the endothelial Ob-R, generates a growth signal involving a tyrosine kinase-dependent intracellular pathway and promotes angiogenic processes. We speculate that this leptin-mediated stimulation of angiogenesis might represent not only a key event in the settlement of obesity but also may contribute to the modulation of growth under physiological and pathophysiological conditions in other tissues.
Key Words: obesity • adipocyte • growth • cytokine
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J. Li, X. Yu, W. Pan, and R. H. Unger Gene expression profile of rat adipose tissue at the onset of high-fat-diet obesity Am J Physiol Endocrinol Metab, June 1, 2002; 282(6): E1334 - E1341. [Abstract] [Full Text] [PDF]
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P. Quehenberger, M. Exner, R. Sunder-Plassmann, K. Ruzicka, C. Bieglmayer, G. Endler, C. Muellner, W. Speiser, and O. Wagner Leptin Induces Endothelin-1 in Endothelial Cells In Vitro Circ. Res., April 5, 2002; 90(6): 711 - 718. [Abstract] [Full Text] [PDF]
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G. J. Mick, X. Wang, and K. McCormick White Adipocyte Vascular Endothelial Growth Factor: Regulation by Insulin Endocrinology, March 1, 2002; 143(3): 948 - 953. [Abstract] [Full Text] [PDF]
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P. Vigano, E. Somigliana, R. Matrone, A. Dubini, C. Barron, M. Vignali, and A. M. di Blasio Serum Leptin Concentrations in Endometriosis J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1085 - 1087. [Abstract] [Full Text] [PDF]
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 K. Kume, K. Satomura, S. Nishisho, E. Kitaoka, K. Yamanouchi, S. Tobiume, and M. Nagayama Potential Role of Leptin in Endochondral Ossification J. Histochem. Cytochem., February 1, 2002; 50(2): 159 - 170. [Abstract] [Full Text] [PDF]
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 A. Wiecek, F. Kokot, J. Chudek, and M. Adamczak The adipose tissue--a novel endocrine organ of interest to the nephrologist Nephrol. Dial. Transplant., February 1, 2002; 17(2): 191 - 195. [Full Text] [PDF]
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 D. R. Harder, C. Zhang, and D. Gebremedhin Astrocytes Function in Matching Blood Flow to Metabolic Activity Physiology, February 1, 2002; 17(1): 27 - 31. [Abstract] [Full Text] [PDF]
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A. Glasow, W. Kiess, U. Anderegg, A. Berthold, A. Bottner, and J. Kratzsch Expression of Leptin (Ob) and Leptin Receptor (Ob-R) in Human Fibroblasts: Regulation of Leptin Secretion by Insulin J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4472 - 4479. [Abstract] [Full Text] [PDF]
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A. Bouloumie, C. Sengenes, G. Portolan, J. Galitzky, and M. Lafontan Adipocyte Produces Matrix Metalloproteinases 2 and 9: Involvement in Adipose Differentiation Diabetes, September 1, 2001; 50(9): 2080 - 2086. [Abstract] [Full Text] [PDF]
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M. Winnicki, B. G. Phillips, V. Accurso, P. van de Borne, A. Shamsuzzaman, K. Patil, K. Narkiewicz, and V. K. Somers Independent Association Between Plasma Leptin Levels and Heart Rate in Heart Transplant Recipients Circulation, July 24, 2001; 104(4): 384 - 386. [Abstract] [Full Text] [PDF]
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H. Yamashita, J. Shao, T. Ishizuka, P. J. Klepcyk, P. Muhlenkamp, L. Qiao, N. Hoggard, and J. E. Friedman Leptin Administration Prevents Spontaneous Gestational Diabetes in Heterozygous Leprdb/+ Mice: Effects on Placental Leptin and Fetal Growth Endocrinology, July 1, 2001; 142(7): 2888 - 2897. [Abstract] [Full Text] [PDF]
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 F. LARCHER, M. DEL RIO, F. SERRANO, J. C. SEGOVIA, A. RAMIREZ, A. MEANA, A. PAGE, J. L. ABAD, M. A. GONZALEZ, J. BUEREN, et al. A cutaneous gene therapy approach to human leptin deficiencies: correction of the murine ob/ob phenotype using leptin-targeted keratinocyte grafts FASEB J, July 1, 2001; 15(9): 1529 - 1538. [Abstract] [Full Text] [PDF]
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 H. Koshiba, J. Kitawaki, H. Ishihara, N. Kado, I. Kusuki, K. Tsukamoto, and H. Honjo Progesterone inhibition of functional leptin receptor mRNA expression in human endometrium Mol. Hum. Reprod., June 1, 2001; 7(6): 567 - 572. [Abstract] [Full Text] [PDF]
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G. De Placido, C. Alviggi, C. Carravetta, M.L. Pisaturo, V. Sanna, M. Wilding, G.M. Lord, and G. Matarese The peritoneal fluid concentration of leptin is increased in women with peritoneal but not ovarian endometriosis Hum. Reprod., June 1, 2001; 16(6): 1251 - 1254. [Abstract] [Full Text] [PDF]
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R. Cao, E. Brakenhielm, C. Wahlestedt, J. Thyberg, and Y. Cao Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF PNAS, May 3, 2001; (2001) 101564798. [Abstract] [Full Text]
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J. A. Pasco, M. J. Henry, M. A. Kotowicz, G. R. Collier, M. J. Ball, A. M. Ugoni, and G. C. Nicholson Serum Leptin Levels Are Associated with Bone Mass in Nonobese Women J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 1884 - 1887. [Abstract] [Full Text]
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B. Winters, Z. Mo, E. Brooks-Asplund, S. Kim, A. Shoukas, D. Li, D. Nyhan, and D. E. Berkowitz Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lepob) mice J Appl Physiol, December 1, 2000; 89(6): 2382 - 2390. [Abstract] [Full Text] [PDF]
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P. Trayhurn, J. S. Duncan, A. M. Wood, and J. H. Beattie Metallothionein gene expression and secretion in white adipose tissue Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2000; 279(6): R2329 - R2335. [Abstract] [Full Text] [PDF]
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K. Linnemann, A. Malek, R. Sager, W. F. Blum, H. Schneider, and C. Fusch Leptin Production and Release in the Dually in VitroPerfused Human Placenta J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4298 - 4301. [Abstract] [Full Text]
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M. C. Henson and V. D. Castracane Leptin in Pregnancy Biol Reprod, November 1, 2000; 63(5): 1219 - 1228. [Abstract] [Full Text]
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 G. Fantuzzi and R. Faggioni Leptin in the regulation of immunity, inflammation, and hematopoiesis J. Leukoc. Biol., October 1, 2000; 68(4): 437 - 446. [Abstract] [Full Text]
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H Mix, A Widjaja, O Jandl, M Cornberg, A Kaul, M Goke, W Beil, M Kuske, G Brabant, M P Manns, et al. Expression of leptin and leptin receptor isoforms in the human stomach Gut, October 1, 2000; 47(4): 481 - 486. [Abstract] [Full Text] [PDF]
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R. F. Gariano, A. K. Nath, D. J. D’Amico, T. Lee, and M. R. Sierra–Honigmann Elevation of Vitreous Leptin in Diabetic Retinopathy and Retinal Detachment Invest. Ophthalmol. Vis. Sci., October 1, 2000; 41(11): 3576 - 3581. [Abstract] [Full Text]
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G. Matarese, C. Alviggi, V. Sanna, J. K. Howard, G. M. Lord, C. Carravetta, S. Fontana, R. I. Lechler, S. R. Bloom, and G. De Placido Increased Leptin Levels in Serum and Peritoneal Fluid of Patients with Pelvic Endometriosis J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2483 - 2487. [Abstract] [Full Text]
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J. Alfer, F. Muller-Schottle, I. Classen-Linke, U. von Rango, L. Happel, K. Beier-Hellwig, W. Rath, and H. M. Beier The endometrium as a novel target for leptin: differences in fertility and subfertility Mol. Hum. Reprod., July 1, 2000; 6(7): 595 - 601. [Abstract] [Full Text] [PDF]
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W. A. Banks, C. M. Clever, and C. L. Farrell Partial saturation and regional variation in the blood-to-brain transport of leptin in normal weight mice Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E1158 - E1165. [Abstract] [Full Text] [PDF]
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A. Z. Zhao, M. M. Shinohara, D. Huang, M. Shimizu, H. Eldar-Finkelman, E. G. Krebs, J. A. Beavo, and K. E. Bornfeldt Leptin Induces Insulin-like Signaling That Antagonizes cAMP Elevation by Glucagon in Hepatocytes J. Biol. Chem., April 6, 2000; 275(15): 11348 - 11354. [Abstract] [Full Text] [PDF]
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G. Uckaya, M. Ozata, A. Sonmez, C. Kinalp, T. Eyileten, N. Bingol, B. Koc, F. Kocabalkan, and I. C. Ozdemir Is Leptin Associated with Hypertensive Retinopathy? J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 683 - 687. [Abstract] [Full Text]
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P. Sinnaeve, O. Varenne, D. Collen, and S. Janssens Gene therapy in the cardiovascular system: an update Cardiovasc Res, December 1, 1999; 44(3): 498 - 506. [Abstract] [Full Text] [PDF]
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A. BOULOUMIÉ, T. MARUMO, M. LAFONTAN, and R. BUSSE Leptin induces oxidative stress in human endothelial cells FASEB J, July 1, 1999; 13(10): 1231 - 1238. [Abstract] [Full Text]
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