Hypoxia-induced pulmonary vascular remodeling: a model for what human disease?

Exposure of most animals to low levels of environmental oxygen results in alveolar hypoxia and reliably causes chronic pulmonary hypertension and morphological alterations of the precapillary pulmonary vessels (1–4). Chronic hypoxic exposure of animals has been used for decades to induce pulmonary vascular remodeling and, more recently, to assess the roles in this process of lipid mediators (5), endothelin (6), serotonin (7), nitric oxide (NO) (8, 9), and prostacyclin (10), as well as VEGF and its receptors (11, 12). As one measure of the clinical importance of work in this system, trials are now ongoing to test endothelin receptor blockers in the treatment of severe pulmonary hypertension.

[1]  P. Hirth,et al.  Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death‐dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  G. Semenza.  Surviving ischemia: adaptive responses mediated by hypoxia-inducible factor 1. , 2000, The Journal of clinical investigation.

[3]  J. Isner,et al.  Tissue responses to ischemia: local and remote responses for preserving perfusion of ischemic muscle. , 2000, The Journal of clinical investigation.

[4]  K. Lesch,et al.  Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. , 2000, The Journal of clinical investigation.

[5]  Adrian M Heilbut,et al.  Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor , 2000, Nature Medicine.

[6]  C. White,et al.  Mechanisms of cell injury and death in hyperoxia: role of cytokines and Bcl-2 family proteins. , 2000, American journal of respiratory cell and molecular biology.

[7]  Y. Zou,et al.  Protein kinase C-beta and oxygen deprivation. A novel Egr-1-dependent pathway for fibrin deposition in hypoxemic vasculature. , 2000, The Journal of biological chemistry.

[8]  K. Morris,et al.  Mechanism of hypoxic pulmonary vasoconstriction involves ET(A) receptor-mediated inhibition of K(ATP) channel. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[9]  P. Jones,et al.  Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. , 2000, The Journal of clinical investigation.

[10]  R. Wadsworth,et al.  Superoxide in the pulmonary circulation. , 1999, Pharmacology & therapeutics.

[11]  D. Y. Lee,et al.  Vascular Endothelial Growth Factor Governs Endothelial Nitric-oxide Synthase Expression via a KDR/Flk-1 Receptor and a Protein Kinase C Signaling Pathway* , 1999, The Journal of Biological Chemistry.

[12]  N. Voelkel,et al.  Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. , 1999, The Journal of clinical investigation.

[13]  T. Beaty,et al.  Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. , 1999, The Journal of clinical investigation.

[14]  E. Hoffman,et al.  Interstitial lung disease: A quantitative study using the adaptive multiple feature method. , 1999, American journal of respiratory and critical care medicine.

[15]  P. Huang,et al.  The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. , 1999, The Journal of clinical investigation.

[16]  ChengXiang Zhai,et al.  Tissue factor transcription driven by Egr-1 is a critical mechanism of murine pulmonary fibrin deposition in hypoxia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  N. Voelkel,et al.  Pulmonary hypertension and inflammation. , 1998, The Journal of laboratory and clinical medicine.

[18]  K. Shroyer,et al.  Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. , 1998, The Journal of clinical investigation.

[19]  M. Gassmann,et al.  Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. , 1998, Genes & development.

[20]  I. Zachary,et al.  Vascular endothelial growth factor stimulates prostacyclin production and activation of cytosolic phospholipase A2 in endothelial cells via p42/p44 mitogen‐activated protein kinase , 1997, FEBS letters.

[21]  C K Breuer,et al.  Tissue-engineered heart valves. Autologous valve leaflet replacement study in a lamb model. , 1996, Circulation.

[22]  G. Semenza,et al.  Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1 , 1996, Molecular and cellular biology.

[23]  B. Koller,et al.  Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats. , 1996, The Journal of clinical investigation.

[24]  S. E. Brodie.  New York, New York, USA , 1996 .

[25]  J. Stone,et al.  Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity , 1995, Nature Medicine.

[26]  G. Semenza,et al.  Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Frangos,et al.  Regulation of vascular tone. , 1995, Canadian journal of physiology and pharmacology.

[28]  N. Voelkel,et al.  Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. , 1995, The Journal of clinical investigation.

[29]  S. Oparil,et al.  Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. , 1994, Journal of applied physiology.

[30]  S. Archer,et al.  Increased endothelium-derived NO in hypertensive pulmonary circulation of chronically hypoxic rats. , 1994, Journal of applied physiology.

[31]  M. Blaustein,et al.  Hypoxia reduces potassium currents in cultured rat pulmonary but not mesenteric arterial myocytes. , 1993, The American journal of physiology.

[32]  G. Semenza,et al.  A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation , 1992, Molecular and cellular biology.

[33]  T. Allen,et al.  Transforming growth factor beta 1 promotes the differentiation of endothelial cells into smooth muscle-like cells in vitro. , 1992, Journal of cell science.

[34]  N. Voelkel,et al.  PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats. , 1992, Journal of applied physiology.

[35]  N. Voelkel,et al.  Prostaglandin and leukotriene production by alveolar type II cells in vitro. , 1990, The American journal of physiology.

[36]  N. Voelkel,et al.  Severe pulmonary hypertension and arterial adventitial changes in newborn calves at 4,300 m. , 1987, Journal of applied physiology.

[37]  K. Morris,et al.  Prevention and reversal of hypoxic pulmonary hypertension by calcium antagonists. , 1984, The American review of respiratory disease.

[38]  A. Nadas,et al.  Rat pulmonary circulation after chronic hypoxia: hemodynamic and structural features. , 1979, The American journal of physiology.

[39]  N. Völkel,et al.  A kinetic study of lung DNA-synthesis during simulated chronic high altitude hypoxia. , 1977, Thorax.

[40]  J. Arias-Stella,et al.  The Terminal Portion of the Pulmonary Arterial Tree in People Native to High Altitudes , 1963, Circulation.

[41]  D. H. Will,et al.  High Altitude‐Induced Pulmonary Hypertension in Normal Cattle , 1962, Circulation research.