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Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
08:02

Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice

Published on: October 19, 2013

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Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation

Jason Boehme1, Xutong Sun2, Kathryn V Tormos1

  • 1Department of Pediatrics, University of California San Francisco, San Francisco, California.

American Journal of Physiology. Heart and Circulatory Physiology
|September 4, 2016
PubMed

Insights

Pulmonary arterial hypertension (PAH) involves vascular cell overgrowth and metabolic changes. Early in pulmonary overcirculation, smooth muscle cells show increased proliferation and a unique metabolic profile, suggesting NADPH oxidase inhibition as a potential therapy.

Area of Science:

  • Cardiovascular Research
  • Cellular Metabolism
  • Pediatric Cardiology

Background:

  • Pulmonary arterial hypertension (PAH) pathophysiology involves vascular cell hyperproliferation and metabolic reprogramming.
  • Increased pulmonary blood flow (PBF) due to congenital heart disease (CHD) is a key cause of PAH in children.
  • Early metabolic and proliferative changes in pulmonary artery smooth muscle cells (PASMCs) in response to PBF are not well understood.

Purpose of the Study:

  • To investigate early changes in PASMC proliferation and metabolism in a model of pulmonary overcirculation.
  • To characterize the metabolic profile of PASMCs under conditions mimicking pediatric PAH.
  • To explore potential therapeutic targets for preventing PAH in CHD.

Main Methods:

  • Utilized a unique ovine model of pulmonary overcirculation (shunt) to study lambs at 4 weeks of age.
  • Assessed PASMC proliferation rates and mitochondrial function (oxygen consumption, membrane potential, TCA cycle).
  • Analyzed glycolytic lactate production, pentose phosphate pathway (PPP) flux, and NADPH oxidase (Nox) activity.

Main Results:

  • Shunt PASMCs exhibited increased proliferation rates, similar to adult PAH.
  • Mitochondrial function and tricarboxylic acid (TCA) cycle function were decreased, suggesting a Warburg effect.
  • Unexpectedly, shunt PASMCs showed decreased lactate production, increased Nox activity, and reduced NADPH/NADP+ ratios.
  • Pharmacological Nox inhibition preferentially slowed shunt PASMC growth in vitro.

Conclusions:

  • PASMC hyperproliferation occurs early in pulmonary overcirculation, preceding advanced PAH.
  • The metabolic profile in early PAH is unique, characterized by increased Nox activity and PPP flux, independent of HIF-1α or increased glycolysis.
  • Nox inhibition may represent a novel therapeutic strategy to prevent PAH in children with CHD.

Keywords:
ROSglycolysismitochondriaoxygen consumptionpulmonary overcirculation

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