Am. J. Respir. Crit. Care Med., Volume 158, Number 6, December 1998, 1757-1762

Hypoxia Enhances Cellular Proliferation and Inositol 1,4,5-Triphosphate Generation in Fibroblasts from Bovine Pulmonary Artery But Not from Mesenteric Artery

DAVID J. WELSH, PAMELA SCOTT, ROBIN PLEVIN, RODGER WADSWORTH, and ANDREW J. PEACOCK

Pulmonary Vascular Unit, Department of Respiratory Medicine, Western Infirmary, and Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, United Kingdom

When pulmonary hypertension occurs in the face of hypoxia there is remodeling of all three layers of the pulmonary vessels, but in particular, there is an increase in number of adventitial fibroblasts. Hypoxia causes vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. We hypothesized that there are fundamental differences in oxygen sensing and cell signaling between systemic and pulmonary artery cells in response to hypoxia. Here, we determined the effect of hypoxia either alone or in combination with known growth factors such as serum, endothelin-1 (ET-1), and platelet-derived growth factor (PDGF) on the proliferative responses of bovine pulmonary artery and mesenteric artery fibroblasts. Fibroblasts were obtained from primary cultures. Growth was assessed by [³H]thymidine incorporation. Inositol 1,4,5-triphosphate (IP₃) generation was measured using a competitive binding assay. Hypoxia alone increased proliferation of pulmonary artery fibroblasts (611 ± 24%), but not in those from the mesentery. Furthermore, hypoxia had the effect of increasing the replicative response of pulmonary fibroblasts to serum and PDGF, but no change was observed in the mesenteric cells. ET-1 had no effect on growth of either cell type. PDGF gave rise to a significant elevation in IP₃ production under hypoxic conditions in the pulmonary artery cells (234%), but not in the mesenteric cells. ET-1 caused no change in IP₃ production in any cell type. These data suggest that hypoxia sensitizes pulmonary artery fibroblasts to the proliferative effect of mitogens through a pathway that is not present, or is present but repressed, in the mesenteric cells.

This article has been cited by other articles:

				L. Moreno-Vinasco, M. Gomberg-Maitland, M. L. Maitland, A. A. Desai, P. A. Singleton, S. Sammani, L. Sam, Y. Liu, A. N. Husain, R. M. Lang, et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension Physiol Genomics, April 1, 2008; 33(2): 278 - 291. [Abstract] [Full Text] [PDF]

				C. M. Carlin, A. J. Peacock, and D. J. Welsh Fluvastatin Inhibits Hypoxic Proliferation and p38 MAPK Activity in Pulmonary Artery Fibroblasts Am. J. Respir. Cell Mol. Biol., October 1, 2007; 37(4): 447 - 456. [Abstract] [Full Text] [PDF]

				O. Pak, A. Aldashev, D. Welsh, and A. Peacock The effects of hypoxia on the cells of the pulmonary vasculature Eur. Respir. J., August 1, 2007; 30(2): 364 - 372. [Abstract] [Full Text] [PDF]

				N. Koulmann, V. Novel-Chate, A. Peinnequin, R. Chapot, B. Serrurier, N. Simler, H. Richard, R. Ventura-Clapier, and X. Bigard Cyclosporin A Inhibits Hypoxia-induced Pulmonary Hypertension and Right Ventricle Hypertrophy Am. J. Respir. Crit. Care Med., September 15, 2006; 174(6): 699 - 705. [Abstract] [Full Text] [PDF]

				K. R. Stenmark, N. Davie, M. Frid, E. Gerasimovskaya, and M. Das Role of the Adventitia in Pulmonary Vascular Remodeling Physiology, April 1, 2006; 21(2): 134 - 145. [Abstract] [Full Text] [PDF]

				I. R. Preston, N. S. Hill, R. R. Warburton, and B. L. Fanburg Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L367 - L374. [Abstract] [Full Text] [PDF]

				D. Welsh, H. Mortimer, A. Kirk, and A. Peacock The Role of p38 Mitogen-Activated Protein Kinase in Hypoxia-Induced Vascular Cell Proliferation: An Interspecies Comparison Chest, December 1, 2005; 128(6_suppl): 573S - 574S. [Full Text] [PDF]

				X. Yang, K. K. K. Sheares, N. Davie, P. D. Upton, G. W. Taylor, J. Horsley, J. Wharton, and N. W. Morrell Hypoxic Induction of Cox-2 Regulates Proliferation of Human Pulmonary Artery Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., December 1, 2002; 27(6): 688 - 696. [Abstract] [Full Text] [PDF]

				E. V. Gerasimovskaya, S. Ahmad, C. W. White, P. L. Jones, T. C. Carpenter, and K. R. Stenmark Extracellular ATP Is an Autocrine/Paracrine Regulator of Hypoxia-induced Adventitial Fibroblast Growth. SIGNALING THROUGH EXTRACELLULAR SIGNAL-REGULATED KINASE-1/2 AND THE Egr-1 TRANSCRIPTION FACTOR J. Biol. Chem., November 15, 2002; 277(47): 44638 - 44650. [Abstract] [Full Text] [PDF]

				M. Das, E. C. Dempsey, J. T. Reeves, and K. R. Stenmark Selective expansion of fibroblast subpopulations from pulmonary artery adventitia in response to hypoxia Am J Physiol Lung Cell Mol Physiol, May 1, 2002; 282(5): L976 - L986. [Abstract] [Full Text] [PDF]

				D. J. WELSH, A. J. PEACOCK, M. MacLEAN, and M. HARNETT Chronic Hypoxia Induces Constitutive p38 Mitogen-activated Protein Kinase Activity That Correlates with Enhanced Cellular Proliferation in Fibroblasts from Rat Pulmonary But Not Systemic Arteries Am. J. Respir. Crit. Care Med., July 15, 2001; 164(2): 282 - 289. [Abstract] [Full Text] [PDF]

				M. Das, D. M. Bouchey, M. J. Moore, D. C. Hopkins, R. A. Nemenoff, and K. R. Stenmark Hypoxia-induced Proliferative Response of Vascular Adventitial Fibroblasts Is Dependent on G Protein-mediated Activation of Mitogen-activated Protein Kinases J. Biol. Chem., May 4, 2001; 276(19): 15631 - 15640. [Abstract] [Full Text] [PDF]