WM Maniscalco, RH Watkins, JN Finkelstein and MH Campbell
Department of Pediatrics, Strong Children's Medical Center, University of Rochester, New York, USA.

Destruction of pulmonary endothelial cells is characteristic of hyperoxic lung injury. During recovery from hyperoxia, pulmonary endothelial cells proliferate to regenerate the vascular endothelium. Vascular endothelial growth factor (VEGF) is a peptide growth factor that is mitogenic specifically for endothelial cells. We hypothesized that VEGF messenger RNA (mRNA) increases during recovery from acute hyperoxic lung injury. Adult rabbits were exposed to 100% oxygen for 64 h and allowed to recover in air for 0, 1, 3, and 5 days. In situ hybridization showed increased VEGF expression in alveolar epithelial cells beginning at 1 day recovery. By 3 days recovery the message was in alveolar epithelial cells throughout the lung. Compared with alveolar epithelial cells, little or no expression was noted in large vessel endothelial cells, airway cells, or smooth muscle cells. Combined in situ hybridization for VEGF and immunostaining for macrophages and other mesenchymal cells found no VEGF message in those cell types. Isolated alveolar macrophages had no detectable VEGF message. Cells expressing VEGF mRNA were enriched in alveolar type II cell preparations from recovering lung. Double in situ hybridization for VEGF and surfactant protein-C (SP-C) showed co-expression in a population of type II cells, but with an inverse relationship: cells with abundant VEGF mRNA did not have abundant SP-C mRNA. Type II cells in vitro expressed VEGF message, but only when the SP-C message abundance was relatively low. We conclude that alveolar type II cells express increased VEGF mRNA during recovery from acute hyperoxia. These findings are consistent with a role for VEGF in regulating microvascular endothelial repair after oxidant injury.

This article has been cited by other articles:

				R Zhai, M N Gong, W Zhou, T B Thompson, P Kraft, L Su, and D C Christiani Genotypes and haplotypes of the VEGF gene are associated with higher mortality and lower VEGF plasma levels in patients with ARDS Thorax, August 1, 2007; 62(8): 718 - 722. [Abstract] [Full Text] [PDF]

				B. Thebaud and S. H. Abman Bronchopulmonary Dysplasia: Where Have All the Vessels Gone? Roles of Angiogenic Growth Factors in Chronic Lung Disease Am. J. Respir. Crit. Care Med., May 15, 2007; 175(10): 978 - 985. [Abstract] [Full Text] [PDF]

				M. Yee, P. F. Vitiello, J. M. Roper, R. J. Staversky, T. W. Wright, S. A. McGrath-Morrow, W. M. Maniscalco, J. N. Finkelstein, and M. A. O'Reilly Type II epithelial cells are critical target for hyperoxia-mediated impairment of postnatal lung development Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L1101 - L1111. [Abstract] [Full Text] [PDF]

				T. Mirzapoiazova, I. Kolosova, P. V. Usatyuk, V. Natarajan, and A. D. Verin Diverse effects of vascular endothelial growth factor on human pulmonary endothelial barrier and migration Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L718 - L724. [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]

				S. J. Cho, C. L. S. George, J. M. Snyder, and M. J. Acarregui Retinoic Acid and Erythropoietin Maintain Alveolar Development in Mice Treated with an Angiogenesis Inhibitor Am. J. Respir. Cell Mol. Biol., December 1, 2005; 33(6): 622 - 628. [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]

				M. Mura, C. C. dos Santos, D. Stewart, and M. Liu Vascular endothelial growth factor and related molecules in acute lung injury J Appl Physiol, November 1, 2004; 97(5): 1605 - 1617. [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]

				M. M. Kilani, K. A. Mohammed, N. Nasreen, J. A. Hardwick, M. H. Kaplan, R. S. Tepper, and V. B. Antony Respiratory Syncytial Virus Causes Increased Bronchial Epithelial Permeability Chest, July 1, 2004; 126(1): 186 - 191. [Abstract] [Full Text] [PDF]

				N.F. Voelkel and C.D. Cool Pulmonary vascular involvement in chronic obstructive pulmonary disease Eur. Respir. J., November 2, 2003; 22(46_suppl): 28S - 32s. [Abstract] [Full Text] [PDF]

				C. J. Favre, M. Mancuso, K. Maas, J. W. McLean, P. Baluk, and D. M. McDonald Expression of genes involved in vascular development and angiogenesis in endothelial cells of adult lung Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1917 - H1938. [Abstract] [Full Text] [PDF]

				M. A. O'Reilly, R. H. Watkins, R. J. Staversky, and W. M. Maniscalco Induced p21Cip1 in premature baboons with CLD: implications for alveolar hypoplasia Am J Physiol Lung Cell Mol Physiol, October 1, 2003; 285(4): L964 - L971. [Abstract] [Full Text] [PDF]

				J. M. Roper, R. J. Staversky, J. N. Finkelstein, P. C. Keng, and M. A. O'Reilly Identification and isolation of mouse type II cells on the basis of intrinsic expression of enhanced green fluorescent protein Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L691 - L700. [Abstract] [Full Text] [PDF]

				C. E. O. Baleeiro, S. E. Wilcoxen, S. B. Morris, T. J. Standiford, and R. Paine III Sublethal Hyperoxia Impairs Pulmonary Innate Immunity J. Immunol., July 15, 2003; 171(2): 955 - 963. [Abstract] [Full Text] [PDF]

				M. Hanaoka, Y. Droma, A. Naramoto, T. Honda, T. Kobayashi, and K. Kubo Vascular endothelial growth factor in patients with high-altitude pulmonary edema J Appl Physiol, May 1, 2003; 94(5): 1836 - 1840. [Abstract] [Full Text] [PDF]

				W. M. Maniscalco, R. H. Watkins, M. A. O'Reilly, and C. P. Shea Increased epithelial cell proliferation in very premature baboons with chronic lung disease Am J Physiol Lung Cell Mol Physiol, November 1, 2002; 283(5): L991 - L1001. [Abstract] [Full Text] [PDF]

				R. J. Staversky, R. H. Watkins, T. W. Wright, E. Hernady, M. B. LoMonaco, C. T. D'Angio, J. P. Williams, W. M. Maniscalco, and M. A. O'Reilly Normal Remodeling of the Oxygen-Injured Lung Requires the Cyclin-Dependent Kinase Inhibitor p21Cip1/WAF1/Sdi1 Am. J. Pathol., October 1, 2002; 161(4): 1383 - 1393. [Abstract] [Full Text] [PDF]

				P. Lassus, I. Nupponen, A. Kari, M. Pohjavuori, and S. Andersson Early Postnatal Dexamethasone Decreases Hepatocyte Growth Factor in Tracheal Aspirate Fluid From Premature Infants Pediatrics, October 1, 2002; 110(4): 768 - 771. [Abstract] [Full Text] [PDF]

				A. J. BHATT, G. S. PRYHUBER, H. HUYCK, R. H. WATKINS, L. A. METLAY, and W. M. MANISCALCO Disrupted Pulmonary Vasculature and Decreased Vascular Endothelial Growth Factor, Flt-1, and TIE-2 in Human Infants Dying with Bronchopulmonary Dysplasia Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1971 - 1980. [Abstract] [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]

				M. E. Sunday, K. J. Haley, R. L. Emanuel, J. S. Torday, N. Asokananthan, K. A. Sikorski, I. Tooyama, H. Kimura, T. Renda, and V. Erspamer Fetal Alveolar Epithelial Cells Contain [D-Ala2]-Deltorphin I-like Immunoreactivity . delta - and {micro}-Opiate Receptors Mediate Opposite Effects in Developing Lung Am. J. Respir. Cell Mol. Biol., October 1, 2001; 25(4): 447 - 456. [Abstract] [Full Text] [PDF]

				C. B. Allen, B. K. Schneider, and C. W. White Limitations to oxygen diffusion and equilibration in in vitro cell exposure systems in hyperoxia and hypoxia Am J Physiol Lung Cell Mol Physiol, October 1, 2001; 281(4): L1021 - L1027. [Abstract] [Full Text] [PDF]

				M. A. O'Reilly DNA damage and cell cycle checkpoints in hyperoxic lung injury: braking to facilitate repair Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L291 - L305. [Abstract] [Full Text] [PDF]

				B. Maitre, S. Boussat, D. Jean, M. Gouge, L. Brochard, B. Housset, S. Adnot, and C. Delclaux Vascular endothelial growth factor synthesis in the acute phase of experimental and clinical lung injury Eur. Respir. J., July 1, 2001; 18(1): 100 - 106. [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. G. Lee, H. J. Yoon, Z. Zhu, H. Link, Z. Wang, J. M. Gwaltney Jr., M. Landry, and J. A. Elias Respiratory Syncytial Virus Stimulation of Vascular Endothelial Cell Growth Factor/Vascular Permeability Factor Am. J. Respir. Cell Mol. Biol., November 1, 2000; 23(5): 662 - 669. [Abstract] [Full Text]

				A. Y. Sheikh, J. J. Gibson, M. D. Rollins, H. W. Hopf, Z. Hussain, and T. K. Hunt Effect of Hyperoxia on Vascular Endothelial Growth Factor Levels in a Wound Model Arch Surg, November 1, 2000; 135(11): 1293 - 1297. [Abstract] [Full Text] [PDF]

				S. Boussat, S. Eddahibi, A. Coste, V. Fataccioli, M. Gouge, B. Housset, S. Adnot, and B. Maitre Expression and regulation of vascular endothelial growth factor in human pulmonary epithelial cells Am J Physiol Lung Cell Mol Physiol, August 1, 2000; 279(2): L371 - L378. [Abstract] [Full Text] [PDF]

				J. Lu, T. Kasama, K. Kobayashi, Y. Yoda, F. Shiozawa, M. Hanyuda, M. Negishi, H. Ide, and M. Adachi Vascular Endothelial Growth Factor Expression and Regulation of Murine Collagen-Induced Arthritis J. Immunol., June 1, 2000; 164(11): 5922 - 5927. [Abstract] [Full Text] [PDF]

				P. M. Becker, A. Alcasabas, A. Y. Yu, G. L. Semenza, and T. E. Bunton Oxygen-Independent Upregulation of Vascular Endothelial Growth Factor and Vascular Barrier Dysfunction during Ventilated Pulmonary Ischemia in Isolated Ferret Lungs Am. J. Respir. Cell Mol. Biol., March 1, 2000; 22(3): 272 - 279. [Abstract] [Full Text]

				S. Saito, N. Yamaji, K. Yasunaga, T. Saito, S.-i. Matsumoto, M. Katoh, S. Kobayashi, and Y. Masuho The Fibronectin Extra Domain A Activates Matrix Metalloproteinase Gene Expression by an Interleukin-1-dependent Mechanism J. Biol. Chem., October 22, 1999; 274(43): 30756 - 30763. [Abstract] [Full Text] [PDF]

				P. LASSUS, A. RISTIMAKI, O. YLIKORKALA, L. VIINIKKA, and S. ANDERSSON Vascular Endothelial Growth Factor in Human Preterm Lung Am. J. Respir. Crit. Care Med., May 1, 1999; 159(5): 1429 - 1433. [Abstract] [Full Text] [PDF]

				R. H. Watkins, C. T. D'Angio, R. M. Ryan, A. Patel, and W. M. Maniscalco Differential expression of VEGF mRNA splice variants in newborn and adult hyperoxic lung injury Am J Physiol Lung Cell Mol Physiol, May 1, 1999; 276(5): L858 - L867. [Abstract] [Full Text] [PDF]

				M. J. Acarregui, S. T. Penisten, K. L. Goss, K. Ramirez, and J. M. Snyder Vascular Endothelial Growth Factor Gene Expression in Human Fetal Lung In Vitro Am. J. Respir. Cell Mol. Biol., January 1, 1999; 20(1): 14 - 23. [Abstract] [Full Text]

				M. A. O'Reilly, R. J. Staversky, R. H. Watkins, and W. M. Maniscalco Accumulation of p21Cip1/WAF1 during Hyperoxic Lung Injury in Mice Am. J. Respir. Cell Mol. Biol., November 1, 1998; 19(5): 777 - 785. [Abstract] [Full Text]

				C. G. Kevil, D. K. Payne, E. Mire, and J. S. Alexander Vascular Permeability Factor/Vascular Endothelial Cell Growth Factor-mediated Permeability Occurs through Disorganization of Endothelial Junctional Proteins J. Biol. Chem., June 12, 1998; 273(24): 15099 - 15103. [Abstract] [Full Text] [PDF]

				W. M. Maniscalco, R. H. Watkins, P. R. Chess, R. A. Sinkin, S. Horowitz, and L. Toia Cell-specific expression of fibronectin and EIIIA and EIIIB splice variants after oxygen injury Am J Physiol Lung Cell Mol Physiol, April 1, 1998; 274(4): L599 - L609. [Abstract] [Full Text] [PDF]

				W. M. Maniscalco, R. H. Watkins, G. S. Pryhuber, A. Bhatt, C. Shea, and H. Huyck Angiogenic factors and alveolar vasculature: development and alterations by injury in very premature baboons Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L811 - L823. [Abstract] [Full Text] [PDF]