This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Klekamp, J. G. Articles by Perkett, E. A. Search for Related Content PubMed PubMed Citation Articles by Klekamp, J. G. Articles by Perkett, E. A.

(American Journal of Pathology. 1999;154:823-831.)
© 1999 American Society for Investigative Pathology

Regular Articles

Exposure to Hyperoxia Decreases the Expression of Vascular Endothelial Growth Factor and Its Receptors in Adult Rat Lungs

Jessica G. Klekamp* , Kasia Jarzecka and Elizabeth A. Perkett

From the Departments of Critical Care * and Pediatric Pulmonary Medicine, Vanderbilt University, Nashville, Tennessee

Exposure to high levels of inspired oxygen leads to respiratory failure and death in many animal models. Endothelial cell death is an early finding, before the onset of respiratory failure. Vascular endothelial growth factor (VEGF) is highly expressed in the lungs of adult animals. In the present study, adult Sprague-Dawley rats were exposed to >95% FiO₂ for 24 or 48 hours. Northern blot analysis revealed a marked reduction in VEGF mRNA abundance by 24 hours, which decreased to less than 50% of control by 48 hours. In situ hybridization revealed that VEGF was highly expressed in distal airway epithelial cells in controls but disappeared in the oxygen-exposed animals. Immunohistochemistry and Western blot analyses demonstrated that VEGF protein was decreased at 48 hours. TUNEL staining demonstrated the presence of apoptotic cells coincident with the decline in VEGF. Abundance of VEGF receptor mRNAs (Flt-1 and KDR/Flk) decreased in the late time points of the study (48 hours), possibly secondary to the loss of endothelial cells. We speculate that VEGF functions as a survival factor in the normal adult rat lung, and its loss during hyperoxia contributes to the pathophysiology of oxygen-induced lung damage.

This article has been cited by other articles:

				S. H. Abman The Dysmorphic Pulmonary Circulation in Bronchopulmonary Dysplasia: A Growing Story Am. J. Respir. Crit. Care Med., July 15, 2008; 178(2): 114 - 115. [Full Text] [PDF]

				D. Xu, R. E. Perez, I. I. Ekekezie, A. Navarro, and W. E. Truog Epidermal growth factor-like domain 7 protects endothelial cells from hyperoxia-induced cell death Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L17 - L23. [Abstract] [Full Text] [PDF]

				J. Gien, G. J. Seedorf, V. Balasubramaniam, N. Markham, and S. H. Abman Intrauterine Pulmonary Hypertension Impairs Angiogenesis In Vitro: Role of Vascular Endothelial Growth Factor Nitric Oxide Signaling Am. J. Respir. Crit. Care Med., December 1, 2007; 176(11): 1146 - 1153. [Abstract] [Full Text] [PDF]

				J.-R. Tang, G. Seedorf, V. Balasubramaniam, A. Maxey, N. Markham, and S. H. Abman Early inhaled nitric oxide treatment decreases apoptosis of endothelial cells in neonatal rat lungs after vascular endothelial growth factor inhibition Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1271 - L1280. [Abstract] [Full Text] [PDF]

				J. M. Siner, G. Jiang, Z. I. Cohen, P. Shan, X. Zhang, C. G. Lee, J. A. Elias, and P. J. Lee VEGF-induced heme oxygenase-1 confers cytoprotection from lethal hyperoxia in vivo FASEB J, May 1, 2007; 21(7): 1422 - 1432. [Abstract] [Full Text] [PDF]

				M. K. Sakurai, S. Lee, D. A. Arsenault, V. Nose, J. M. Wilson, J. V. Heymach, and M. Puder Vascular endothelial growth factor accelerates compensatory lung growth after unilateral pneumonectomy Am J Physiol Lung Cell Mol Physiol, March 1, 2007; 292(3): L742 - L747. [Abstract] [Full Text] [PDF]

				A. M. Kunig, V. Balasubramaniam, N. E. Markham, G. Seedorf, J. Gien, and S. H. Abman Recombinant human VEGF treatment transiently increases lung edema but enhances lung structure after neonatal hyperoxia Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L1068 - L1078. [Abstract] [Full Text] [PDF]

				A R L Medford and A B Millar Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): paradox or paradigm? Thorax, July 1, 2006; 61(7): 621 - 626. [Abstract] [Full Text] [PDF]

				N. F. Voelkel, R. W. Vandivier, and R. M. Tuder Vascular endothelial growth factor in the lung Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L209 - L221. [Abstract] [Full Text] [PDF]

				A. M. Kunig, V. Balasubramaniam, N. E. Markham, D. Morgan, G. Montgomery, T. R. Grover, and S. H. Abman Recombinant human VEGF treatment enhances alveolarization after hyperoxic lung injury in neonatal rats Am J Physiol Lung Cell Mol Physiol, October 1, 2005; 289(4): L529 - L535. [Abstract] [Full Text] [PDF]

				L. B. Ware, R. J. Kaner, R. G. Crystal, R. Schane, N. N. Trivedi, D. McAuley, and M. A. Matthay VEGF levels in the alveolar compartment do not distinguish between ARDS and hydrostatic pulmonary oedema Eur. Respir. J., July 1, 2005; 26(1): 101 - 105. [Abstract] [Full Text] [PDF]

				A. R. Albig and W. P. Schiemann Identification and Characterization of Regulator of G Protein Signaling 4 (RGS4) as a Novel Inhibitor of Tubulogenesis: RGS4 Inhibits Mitogen-activated Protein Kinases and Vascular Endothelial Growth Factor Signaling Mol. Biol. Cell, February 1, 2005; 16(2): 609 - 625. [Abstract] [Full Text] [PDF]

				K. Tang, H. B. Rossiter, P. D. Wagner, and E. C. Breen Lung-targeted VEGF inactivation leads to an emphysema phenotype in mice J Appl Physiol, October 1, 2004; 97(4): 1559 - 1566. [Abstract] [Full Text] [PDF]

				Mechanisms and Limits of Induced Postnatal Lung Growth Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 319 - 343. [Full Text] [PDF]

				G. E. Hosford and D. M. Olson Effects of hyperoxia on VEGF, its receptors, and HIF-2{alpha} in the newborn rat lung Am J Physiol Lung Cell Mol Physiol, July 1, 2003; 285(1): L161 - L168. [Abstract] [Full Text] [PDF]

				D.C Felmeden, A.D Blann, and G.Y.H Lip Angiogenesis: basic pathophysiology and implications for disease Eur. Heart J., April 1, 2003; 24(7): 586 - 603. [Full Text] [PDF]

				S. Koyama, E. Sato, M. Haniuda, H. Numanami, S. Nagai, and T. Izumi Decreased Level of Vascular Endothelial Growth Factor in Bronchoalveolar Lavage Fluid of Normal Smokers and Patients with Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., August 1, 2002; 166(3): 382 - 385. [Abstract] [Full Text] [PDF]

				N. K. Ozaki, K. D. Beharry, K. C. Nishihara, Y. Akmal, J. G. Ang, R. Sheikh, and H. D. Modanlou Regulation of Retinal Vascular Endothelial Growth Factor and Receptors in Rabbits Exposed to Hyperoxia Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1546 - 1557. [Abstract] [Full Text] [PDF]

				S. H. Abman Bronchopulmonary Dysplasia . ""A Vascular Hypothesis"" Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1755 - 1756. [Full Text] [PDF]

				P. LASSUS, M. TURANLAHTI, P. HEIKKILA, L. C. ANDERSSON, I. NUPPONEN, A. SARNESTO, and S. ANDERSSON Pulmonary Vascular Endothelial Growth Factor and Flt-1 in Fetuses, in Acute and Chronic Lung Disease, and in Persistent Pulmonary Hypertension of the Newborn Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1981 - 1987. [Abstract] [Full Text] [PDF]

				K. C. Meyer, A. L. Cardoni, Z. Xiang, R. D. Cornwell, and R. B. Love Vascular Endothelial Growth Factor in Human Lung Transplantation Chest, January 1, 2001; 119(1): 137 - 143. [Abstract] [Full Text] [PDF]

				C. Barazzone and C. W. White Mechanisms of Cell Injury and Death in Hyperoxia . Role of Cytokines and Bcl-2 Family Proteins Am. J. Respir. Cell Mol. Biol., May 1, 2000; 22(5): 517 - 519. [Full Text]