S100A4 and bone morphogenetic protein-2 codependently induce vascular smooth muscle cell migration via

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Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
08:43

Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation

Published on: May 31, 2016

Edda Spiekerkoetter1, Christophe Guignabert, Vinicio de Jesus Perez

  • 1Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif 94305-5162, USA.

Circulation Research
|August 29, 2009
PubMed
Abstract

Insights

S100A4/Mts1 and Bone Morphogenetic Protein-2 (BMP-2) promote human pulmonary artery smooth muscle cell (hPASMC) migration via a codependent mechanism involving Receptor for Advanced Glycation End Products (RAGE) and Bone Morphogenetic Protein Receptor II (BMPRII). Loss of BMPRII function in pulmonary arterial hypertension may enhance this motility.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cardiovascular Research

Background:

  • S100A4/Mts1 protein is known to influence the motility of human pulmonary artery smooth muscle cells (hPASMCs).
  • This motility is partly mediated through interactions with the receptor for advanced glycation end products (RAGE).
  • Pulmonary arterial hypertension (PAH) is characterized by the loss of function of bone morphogenetic protein receptor II (BMPRII).

Purpose of the Study:

  • To investigate the hypothesis that S100A4/Mts1-mediated hPASMC motility is exacerbated by the loss of BMPRII function.
  • To elucidate the molecular mechanisms underlying the interaction between S100A4/Mts1, BMP-2, RAGE, and BMPRII in hPASMC migration.

Main Methods:

  • Treatment of hPASMCs with S100A4/Mts1 and BMP-2.
  • Utilized anti-RAGE antibodies and BMPRII short interference (si)RNA to assess receptor involvement.
  • Analyzed extracellular signal-regulated kinase (ERK) phosphorylation, matrix metalloproteinase 2 (MMP-2) activity, and intracellular chloride channel 4 (CLIC4) expression.
  • Investigated the role of RhoA and Rac1 GTPases in cell motility.

Main Results:

  • Both S100A4/Mts1 and BMP-2 independently induced hPASMC migration, dependent on both RAGE and BMPRII.
  • ERK phosphorylation, induced by both ligands, was required for motility via MMP-2 activation, with RAGE blocking this pathway.
  • BMPRII siRNA, but not anti-RAGE, reduced CLIC4 expression, affecting cytoskeletal organization and RhoA/Rac1 activation, leading to vacuole formation.

Conclusions:

  • A single ligand (BMP-2 or S100A4/Mts1) can engage multiple cell surface receptors (RAGE, BMPRII) to coordinate signaling pathways.
  • These coordinated signals culminate in a functional cellular response, specifically cell motility.
  • This intricate signaling network, while precise, may be dysregulated in diseases like pulmonary arterial hypertension.

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