Merck
  • Home
  • Search Results
  • Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia.

Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia.

American journal of physiology. Lung cellular and molecular physiology (2014-11-17)
Francis Y Kim, Elizabeth A Barnes, Lihua Ying, Chihhsin Chen, Lori Lee, Cristina M Alvira, David N Cornfield
ABSTRACT

Endothelin-1 (ET-1) increases pulmonary vascular tone through direct effects on pulmonary artery smooth muscle cells (PASMC) via membrane-bound ET-1 receptors. Circulating ET-1 contributes to vascular remodeling by promoting SMC proliferation and migration and inhibiting SMC apoptosis. Although endothelial cells (EC) are the primary source of ET-1, whether ET-1 produced by SMC modulates pulmonary vascular tone is unknown. Using transgenic mice created by crossbreeding SM22α-Cre mice with ET-1(flox/flox) mice to selectively delete ET-1 in SMC, we tested the hypothesis that PASMC ET-1 gene expression modulates the pulmonary vascular response to hypoxia. ET-1 gene deletion and selective activity of SM22α promoter-driven Cre recombinase were confirmed. Functional assays were performed under normoxic (21% O2) or hypoxic (5% O2) conditions using murine PASMC obtained from ET-1(+/+) and ET-1(-/-) mic and in human PASMC (hPASMC) after silencing of ET-1 using siRNA. Under baseline conditions, there was no difference in right ventricular systolic pressure (RVSP) between SM22α-ET-1(-/-) and SM22α-ET-1(+/+) (control) littermates. After exposure to hypoxia (10% O2, 21-24 days), RVSP was and vascular remodeling were less in SM22α-ET-1(-/-) mice compared with control littermates (P < 0.01). Loss of ET-1 decreased PASMC proliferation and migration and increased apoptosis under normoxic and hypoxic conditions. Exposure to selective ET-1 receptor antagonists had no effect on either the hypoxia-induced hPASMC proliferative or migratory response. SMC-specific ET-1 deletion attenuates hypoxia-induced increases in pulmonary vascular tone and structural remodeling. The observation that loss of ET-1 inhibited SMC proliferation, survival, and migration represents evidence that ET-1 derived from SMC plays a previously undescribed role in modulating the response of the pulmonary circulation to hypoxia. Thus PASMC ET-1 may modulate vascular tone independently of ET-1 produced by EC.

MATERIALS
Product Number
Brand
Product Description

Supelco
Glycine, analytical standard, for nitrogen determination according to Kjeldahl method
Supelco
Glycine, certified reference material, TraceCERT®
Supelco
4-tert-Octylphenol monoethoxylate solution, 1 μg/mL in acetone, analytical standard
Supelco
Glycine, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Ethanolamine, purified by redistillation, ≥99.5%
Sigma-Aldrich
Glutaraldehyde solution, 50 wt. % in H2O
Supelco
4-tert-Octylphenol monoethoxylate solution, 10 μg/mL in acetone, analytical standard
Sigma-Aldrich
Glycine, 99%, FCC
Sigma-Aldrich
Glutaraldehyde solution, Grade I, 70% in H2O, specially purified for use as an electron microscopy fixative or other sophisticated use
Sigma-Aldrich
Glutaraldehyde solution, 50% in H2O, suitable for photographic applications
Sigma-Aldrich
Glycine, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, ≥98.5%
Sigma-Aldrich
Glutaraldehyde solution, Grade II, 25% in H2O
Sigma-Aldrich
Endothelin 1, ≥97% (HPLC), powder
Sigma-Aldrich
Glutaraldehyde solution, Grade I, 25% in H2O, specially purified for use as an electron microscopy fixative
Sigma-Aldrich
Glycine, ReagentPlus®, ≥99% (HPLC)
Sigma-Aldrich
Glycine, ACS reagent, ≥98.5%
Sigma-Aldrich
Ethanolamine, ACS reagent, ≥99.0%
Sigma-Aldrich
Glutaric dialdehyde solution, 50 wt. % in H2O, FCC
Sigma-Aldrich
Ethanolamine, ≥98%
Sigma-Aldrich
Glutaraldehyde solution, Grade I, 50% in H2O, specially purified for use as an electron microscopy fixative or other sophisticated use
Sigma-Aldrich
Ethanolamine, liquid, BioReagent, suitable for cell culture, ≥98%
Sigma-Aldrich
Glycine, BioXtra, ≥99% (titration)
Sigma-Aldrich
Glycine, puriss. p.a., reag. Ph. Eur., buffer substance, 99.7-101% (calc. to the dried substance)
Sigma-Aldrich
Glycine, meets analytical specification of Ph. Eur., BP, USP, 99-101% (based on anhydrous substance)
Supelco
Ethanolamine, analytical standard
Sigma-Aldrich
Ethanolamine, puriss. p.a., ACS reagent, ≥99.0% (GC/NT)
Sigma-Aldrich
Glycine, suitable for electrophoresis, ≥99%
Sigma-Aldrich
Glycine, BioUltra, for molecular biology, ≥99.0% (NT)
Sigma-Aldrich
Ethanolamine, ≥99%
Sigma-Aldrich
Glycine, tested according to Ph. Eur.