© 2000 American Heart Association, Inc.
Cellular Biology |
Acidosis Inhibits Endothelial Cell Apoptosis and Function and Induces Basic Fibroblast Growth Factor and Vascular Endothelial Growth Factor Expression
From the Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy, and the Dipartimento di Scienze Morfologico-Biomediche (L.T.), Sezione di Anatomia e Istologia, Università di Verona, Verona, Italy.
Correspondence to Daniela D’Arcangelo, Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, via dei Monti di Creta, 104, 00167 Rome, Italy. E-mail d.darcangelo{at}idi.it
Abstract—Endothelial cells are exposed to an acidotic environment in a variety of pathological and physiological conditions. However, the effect of acidosis on endothelial cell function is still largely unknown, and it was evaluated in the present study. Bovine aortic endothelial cells (BAECs) were grown in bicarbonate buffer equilibrated either with 20% CO2 (pH 7.0, acidosis) or 5% CO2 (pH 7.4, control). Acidosis inhibited BAEC proliferation in 10% FCS, whereas by day 7 in serum-free medium, cell number was 3-fold higher in acidotic cells than in control cells. Serum deprivation enhanced BAEC apoptosis, and apoptotic cell death was markedly inhibited by acidosis. Additionally, acidosis inhibited FCS-stimulated migration in a modified Boyden chamber assay and FCS-stimulated differentiation into capillary-like structures on reconstituted basement membrane proteins. Conditioned media from BAECs cultured for 48 hours either at pH 7.0 or pH 7.4 enhanced BAEC proliferation and migration at pH 7.4, and both effects were more marked with conditioned medium from BAECs grown in acidotic than in control conditions. Acidosis enhanced vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) mRNA expression as well as bFGF secretion, and a blocking bFGF antibody inhibited enhanced BAEC migration in response to conditioned medium from acidotic cells. These results show that acidosis protects endothelial cells from apoptosis and inhibits their proangiogenic behavior despite enhanced VEGF and bFGF mRNA expression and bFGF secretion.
Key Words: acidosis • apoptosis • endothelium • ischemia • growth factors
This article has been cited by other articles:
 |
|
 |
|
  L. V. Yang, C. G. Radu, M. Roy, S. Lee, J. McLaughlin, M. A. Teitell, M. L. Iruela-Arispe, and O. N. Witte Vascular Abnormalities in Mice Deficient for the G Protein-Coupled Receptor GPR4 That Functions as a pH Sensor Mol. Cell. Biol., February 15, 2007; 27(4): 1334 - 1347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kumar, S. Kasseckert, S. Kostin, Y. Abdallah, C. Schafer, A. Kaminski, H. P. Reusch, H. M. Piper, G. Steinhoff, and Y. Ladilov Ischemic acidosis causes apoptosis in coronary endothelial cells through activation of caspase-12 Cardiovasc Res, January 1, 2007; 73(1): 172 - 180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Facchiano, D. D'Arcangelo, K. Russo, V. Fogliano, C. Mennella, R. Ragone, G. Zambruno, V. Carbone, D. Ribatti, C. Peschle, et al. Glycated Fibroblast Growth Factor-2 Is Quickly Produced in Vitro upon Low-Millimolar Glucose Treatment and Detected in Vivo in Diabetic Mice Mol. Endocrinol., November 1, 2006; 20(11): 2806 - 2818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Fujii, Y. Yonemitsu, M. Onimaru, M. Tanii, T. Nakano, K. Egashira, T. Takehara, M. Inoue, M. Hasegawa, H. Kuwano, et al. Nonendothelial Mesenchymal Cell-Derived MCP-1 Is Required for FGF-2-Mediated Therapeutic Neovascularization: Critical Role of the Inflammatory/Arteriogenic Pathway Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2483 - 2489. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D'Arcangelo, V. Ambrosino, M. Giannuzzo, C. Gaetano, and M. C. Capogrossi Axl receptor activation mediates laminar shear stress anti-apoptotic effects in human endothelial cells Cardiovasc Res, September 1, 2006; 71(4): 754 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Christou, N. Bailey, M. S. Kluger, S. A. Mitsialis, and S. Kourembanas Extracellular acidosis induces heme oxygenase-1 expression in vascular smooth muscle cells Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2647 - H2652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-Y. Chang, H.-J. Ko, T.-H. Heo, and C.-Y. Kang Heparan Sulfate Regulates the Antiangiogenic Activity of Endothelial Monocyte-Activating Polypeptide-II at Acidic pH Mol. Pharmacol., May 1, 2005; 67(5): 1534 - 1543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Irie, T. Tatsumi, M. Takamiya, K. Zen, T. Takahashi, A. Azuma, K. Tateishi, T. Nomura, H. Hayashi, N. Nakajima, et al. Carbon Dioxide-Rich Water Bathing Enhances Collateral Blood Flow in Ischemic Hindlimb via Mobilization of Endothelial Progenitor Cells and Activation of NO-cGMP System Circulation, March 29, 2005; 111(12): 1523 - 1529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Hasanbasic, J. Cuerquis, B. Varnum, and M. D. Blostein Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1207 - H1213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. U. Gurkan, C. O'Donnell, R. Brower, E. Ruckdeschel, and P. M. Becker Differential effects of mechanical ventilatory strategy on lung injury and systemic organ inflammation in mice Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L710 - L718. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Goerges and M. A. Nugent Regulation of Vascular Endothelial Growth Factor Binding and Activity by Extracellular pH J. Biol. Chem., May 23, 2003; 278(21): 19518 - 19525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Terminella, K. Tollefson, J. Kroczynski, J. Pelli, and M. Cutaia Inhibition of apoptosis in pulmonary endothelial cells by altered pH, mitochondrial function, and ATP supply Am J Physiol Lung Cell Mol Physiol, December 1, 2002; 283(6): L1291 - L1302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Onimaru, Y. Yonemitsu, M. Tanii, K. Nakagawa, I. Masaki, S. Okano, H. Ishibashi, K. Shirasuna, M. Hasegawa, and K. Sueishi Fibroblast Growth Factor-2 Gene Transfer Can Stimulate Hepatocyte Growth Factor Expression Irrespective of Hypoxia-Mediated Downregulation in Ischemic Limbs Circ. Res., November 15, 2002; 91(10): 923 - 930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D'Arcangelo, C. Gaetano, and M. C. Capogrossi Acidification Prevents Endothelial Cell Apoptosis by Axl Activation Circ. Res., October 4, 2002; 91 (7): e4 - e12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. D. Mongan, J. Capacchione, S. West, J. Karaian, D. Dubois, R. Keneally, and P. Sharma Pyruvate improves redox status and decreases indicators of hepatic apoptosis during hemorrhagic shock in swine Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1634 - H1644. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.A. Kregenow and E.R. Swenson The lung and carbon dioxide: implications for permissive and therapeutic hypercapnia Eur. Respir. J., July 1, 2002; 20(1): 6 - 11. [Full Text] [PDF]
|
|
|
|
|
|
L. Xu, D. Fukumura, and R. K. Jain Acidic Extracellular pH Induces Vascular Endothelial Growth Factor (VEGF) in Human Glioblastoma Cells via ERK1/2 MAPK Signaling Pathway. MECHANISM OF LOW pH-INDUCED VEGF J. Biol. Chem., March 22, 2002; 277(13): 11368 - 11374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. De Marchis, D. Ribatti, C. Giampietri, A. Lentini, D. Faraone, M. Scoccianti, M. C. Capogrossi, and A. Facchiano Platelet-derived growth factor inhibits basic fibroblast growth factor angiogenic properties in vitro and in vivo through its alpha receptor Blood, March 15, 2002; 99(6): 2045 - 2053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Crowther, N. J. Brown, E. T. Bishop, and C. E. Lewis Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors J. Leukoc. Biol., October 1, 2001; 70(4): 478 - 490. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Fukumura, L. Xu, Y. Chen, T. Gohongi, B. Seed, and R. K. Jain Hypoxia and Acidosis Independently Up-Regulate Vascular Endothelial Growth Factor Transcription in Brain Tumors in Vivo Cancer Res., August 1, 2001; 61(16): 6020 - 6024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-S. Lee, E.-J. Moon, S.-W. Lee, M. S. Kim, K.-W. Kim, and Y.-J. Kim Angiogenic Activity of Pyruvic Acid in in Vivo and in Vitro Angiogenesis Models Cancer Res., April 1, 2001; 61(8): 3290 - 3293. [Abstract] [Full Text]
|
|
|
|
|
|
C. Gaetano, A. Catalano, B. Illi, A. Felici, S. Minucci, R. Palumbo, F. Facchiano, A. Mangoni, S. Mancarella, J. Muhlhauser, et al. Retinoids Induce Fibroblast Growth Factor-2 Production in Endothelial Cells via Retinoic Acid Receptor {{alpha}} Activation and Stimulate Angiogenesis In Vitro and In Vivo Circ. Res., March 2, 2001; 88 (4): e38 - e47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Xu and I. J. Fidler Acidic pH-induced Elevation in Interleukin 8 Expression by Human Ovarian Carcinoma Cells Cancer Res., August 1, 2000; 60(16): 4610 - 4616. [Abstract] [Full Text]
|
|
|
|
|
|
M. Clauss and W. Schaper Vascular Endothelial Growth Factor : A Jack-of-All-Trades or a Nonspecific Stress Gene? Circ. Res., February 18, 2000; 86(3): 251 - 252. [Full Text] [PDF]
|
|