The goal of this research is elucidate the role of endothelin-1 (ET-1) and ET receptors in hypoxia-induced pulmonary hypertension. Results of studies over the last 4 years have confirmed the hypothesis that ET-1 gene expression and ET-1 synthesis are selectively enhanced in lungs of rats exposed to hypoxia. Moreover, studies have confirmed that gene expression of the ET-1 receptors, ET-A and ET-B, is concomitantly enhanced in lungs of these animals. Hypoxia-induced upregulation of ET-1, ET-A and ET-B gene expression and ET-1 release have all paralleled functional and histopathologic evidence of the development of pulmonary hypertension. It is believed that ET-1, generated in conditions of hypoxia, acts via a paracrine mechanism on pulmonary ET-A receptors and, through its interaction, plays a fundamental etiologic role in hypoxia-induced pulmonary vasoconstriction, vascular remodelling, and maintenance of chronic pulmonary hypertension. Recently these investigators have demonstrated that selective ET-A receptor antagonists and a combined ET-A+ET-B receptor antagonist can both prevent and reverse acute and chronic hypoxia-induced pulmonary vasoconstriction and pulmonary hypertension. These data define a role for ET-1 as an important mediator of hypoxia-induced pulmonary hypertension.
The specific aims of the current proposal are: 1) To test the hypothesis that ET-1 contributes to acute and chronic hemodynamic and structural adaptations to hypoxia in the rat by activating both ET-A and ET-B receptors. 2) To determine the cellular sites of ET-1 and ET-A and ET-B receptor gene expression under control conditions and in response to hypoxia. 3) To define the cis-regulatory element(s) in the 5' flanking region of the ET-1 gene involved in amplifying transcription of the ET-1 gene during exposure to hypoxia. 4) To identify and characterize the hypoxia-responsive transcription factor protein(s) that regulate ET-1 gene expression in response to hypoxia. Sprague-Dawley rats exposed to hypoxia (10 percent O2 at 1 atm.) or room air will be studies for Specific Aims 1 and 2. Transgenic mice harboring a human prepro-ET-1 promoter/luciferase reporter gene will be studied in Specific Aim 2. Cultured endothelial and smooth muscle cells derived from human and rat pulmonary microvessels and systemic vascular beds will be studied in Specific Aims 3 and 4.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050147-08
Application #
6183485
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1993-05-15
Project End
2002-08-31
Budget Start
2000-09-05
Budget End
2001-08-31
Support Year
8
Fiscal Year
2000
Total Cost
$230,717
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Xing, Dongqi; Li, Peng; Gong, Kaizheng et al. (2012) Endothelial cells overexpressing interleukin-8 receptors reduce inflammatory and neointimal responses to arterial injury. Circulation 125:1533-41
Olave, Nelida; Nicola, Teodora; Zhang, Wei et al. (2012) Transforming growth factor-? regulates endothelin-1 signaling in the newborn mouse lung during hypoxia exposure. Am J Physiol Lung Cell Mol Physiol 302:L857-65
Nicola, Teodora; Ambalavanan, Namasivayam; Zhang, Wei et al. (2011) Hypoxia-induced inhibition of lung development is attenuated by the peroxisome proliferator-activated receptor-? agonist rosiglitazone. Am J Physiol Lung Cell Mol Physiol 301:L125-34
Nicola, Teodora; Hagood, James S; James, Masheika L et al. (2009) Loss of Thy-1 inhibits alveolar development in the newborn mouse lung. Am J Physiol Lung Cell Mol Physiol 296:L738-50
Ambalavanan, Namasivayam; Nicola, Teodora; Hagood, James et al. (2008) Transforming growth factor-beta signaling mediates hypoxia-induced pulmonary arterial remodeling and inhibition of alveolar development in newborn mouse lung. Am J Physiol Lung Cell Mol Physiol 295:L86-95
Ambalavanan, Namasivayam; Nicola, Teodora; Li, Peng et al. (2008) Role of matrix metalloproteinase-2 in newborn mouse lungs under hypoxic conditions. Pediatr Res 63:26-32
Ambalavanan, Namasivayam; Li, Peng; Bulger, Arlene et al. (2007) Endothelin-1 mediates hypoxia-induced increases in vascular collagen in the newborn mouse lung. Pediatr Res 61:559-64
Chen, Yiu-Fai; Feng, Ji-An; Li, Peng et al. (2006) Dominant negative mutation of the TGF-beta receptor blocks hypoxia-induced pulmonary vascular remodeling. J Appl Physiol 100:564-71
Chen, Yiu-Fai; Feng, Ji-An; Li, Peng et al. (2006) Atrial natriuretic peptide-dependent modulation of hypoxia-induced pulmonary vascular remodeling. Life Sci 79:1357-65
Ambalavanan, Namasivayam; Bulger, Arlene; Murphy-Ullrich, Joanne et al. (2005) Endothelin-A receptor blockade prevents and partially reverses neonatal hypoxic pulmonary vascular remodeling. Pediatr Res 57:631-6

Showing the most recent 10 out of 23 publications