Related Experiment Video

Updated: Jun 16, 2025

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

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Phosphatase-independent activity of smooth-muscle calcineurin orchestrates a gene expression program leading to

Paula Sofía Yunes-Leites1,2, Yilin Sun2,3, Sara Martínez-Martínez1,2

  • 1Gene Regulation in Cardiovascular Remodeling and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Plos Biology
|May 14, 2025
PubMed

Insights

Calcineurin (Cn) in smooth muscle cells (SMCs) drives Angiotensin-II (Ang-II) induced hypertension and abdominal aortic aneurysm (AAA). This structural role of SMC calcineurin, independent of phosphatase activity, highlights PAI-1 as a potential therapeutic target for hypertension.

Area of Science:

  • Vascular Biology
  • Cardiovascular Physiology
  • Molecular Medicine

Background:

  • Angiotensin-II (Ang-II) promotes vascular remodeling in hypertension and abdominal aortic aneurysm (AAA).
  • Calcineurin (Cn) phosphatase activity mediates Ang-II-induced AAA, but the specific cell type involved was unknown.
  • Understanding the precise role of Cn in Ang-II-driven vascular pathologies is crucial.

Purpose of the Study:

  • To determine the cell-specific role of calcineurin (Cn) in Angiotensin-II (Ang-II) induced abdominal aortic aneurysm (AAA) and hypertension.
  • To investigate the mechanisms underlying Cn's function in vascular pathophysiology.
  • To identify novel therapeutic targets for Ang-II-mediated cardiovascular diseases.

Main Methods:

  • Generation of smooth muscle cell (SMC)-specific and endothelial cell (EC)-specific Cn-deficient mice (SM-Cn-/- and EC-Cn-/-).
  • Administration of Ang-II to induce hypertension and AAA in genetically modified mice.
  • Analysis of gene expression, protein activity, and vascular contractility.
  • Pharmacological inhibition of PAI-1 (Serpine1 protein).

Main Results:

  • Cn in SMCs, not ECs, is essential for Ang-II-induced AAA.
  • SMC Cn plays a structural role in Ang-II-induced hypertension, independent of its phosphatase activity.
  • Cn signaling in SMCs regulates ~90% of Ang-II-responsive genes in the aorta, impacting SMC contractility.
  • Serpine1 induction by Ang-II, mediated by Smad2 and structural Cn, is critical for hypertension; PAI-1 inhibition regresses hypertension.

Conclusions:

  • Calcineurin in smooth muscle cells is a key mediator of Ang-II-induced vascular pathologies, including AAA and hypertension.
  • Cn's structural, non-enzymatic role in regulating SMC contractility and gene expression is critical.
  • PAI-1 emerges as a significant downstream effector and a potential therapeutic target for hypertension.

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