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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

mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia

Vera P Krymskaya1, Jennifer Snow, Gregory Cesarone

  • 1Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|March 4, 2011
PubMed

Insights

Chronic hypoxia drives pulmonary arterial hypertension (PAH) through mammalian target of rapamycin (mTOR) pathway activation. Inhibiting mTORC1 and mTORC2 signaling reduces pulmonary arterial vascular smooth muscle cell proliferation, offering a potential PAH therapeutic target.

Area of Science:

  • Cardiovascular Biology
  • Cellular Signaling
  • Molecular Medicine

Background:

  • Pulmonary arterial hypertension (PAH) involves vascular remodeling driven by pulmonary arterial vascular smooth muscle (PAVSM) cell proliferation.
  • The precise cellular and molecular mechanisms underlying PAVSM cell proliferation in PAH remain incompletely understood.

Purpose of the Study:

  • To investigate the role of the mammalian target of rapamycin (mTOR) signaling pathway in PAVSM cell proliferation.
  • To determine if mTOR activation is a key factor in the vascular remodeling observed in PAH.

Main Methods:

  • Utilized siRNA to inhibit mTOR signaling in human and rat PAVSM cells.
  • Exposed PAVSM cells to chronic hypoxia in vitro and in vivo.
  • Assessed mTOR phosphorylation (Ser-2481), mTORC1 (S6), and mTORC2 (Akt Ser-473) activity.
  • Measured PAVSM cell proliferation and DNA synthesis.
  • Investigated the effects of rapamycin and metformin on cell proliferation.

Main Results:

  • Chronic hypoxia increased mTOR activity, S6, and Akt phosphorylation, promoting PAVSM cell proliferation.
  • PAVSM cells from chronically hypoxic rats (VSM-H cells) exhibited sustained increases in mTOR activity and proliferation.
  • Inhibition of mTORC1 or mTORC2 signaling significantly reduced VSM-H and hypoxia-induced PAVSM cell proliferation.

Conclusions:

  • Up-regulation of mTOR activity, involving both mTORC1 and mTORC2, is essential for PAVSM cell proliferation induced by chronic hypoxia.
  • mTOR signaling represents a promising therapeutic target for mitigating vascular remodeling in PAH.

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