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J Exp Med. 2016 Mar 7;213(3):451-63. doi: 10.1084/jem.20150688. Epub 2016 Feb 8.

Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis.

Author information

1
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT 06511.
2
Division of Cardiology, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
3
Department of Cardiology, Boston Children's Hospital, Boston, MA 02115.
4
Section of Metabolic Diseases, Children's Hospital of Pennsylvania, Philadelphia, PA 19104.
5
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261.
6
Department of Surgery, School of Medicine, Yale University, New Haven, CT 06511.
7
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT 06511 daniel.greif@yale.edu.

Abstract

The aorta is the largest artery in the body, yet processes underlying aortic pathology are poorly understood. The arterial media consists of circumferential layers of elastic lamellae and smooth muscle cells (SMCs), and many arterial diseases are characterized by defective lamellae and excess SMCs; however, a mechanism linking these pathological features is lacking. In this study, we use lineage and genetic analysis, pharmacological inhibition, explant cultures, and induced pluripotent stem cells (iPSCs) to investigate supravalvular aortic stenosis (SVAS) patients and/or elastin mutant mice that model SVAS. These experiments demonstrate that multiple preexisting SMCs give rise to excess aortic SMCs in elastin mutants, and these SMCs are hyperproliferative and dedifferentiated. In addition, SVAS iPSC-derived SMCs and the aortic media of elastin mutant mice and SVAS patients have enhanced integrin β3 levels, activation, and downstream signaling, resulting in SMC misalignment and hyperproliferation. Reduced β3 gene dosage in elastin-null mice mitigates pathological aortic muscularization, SMC misorientation, and lumen loss and extends survival, which is unprecedented. Finally, pharmacological β3 inhibition in elastin mutant mice and explants attenuates aortic hypermuscularization and stenosis. Thus, integrin β3-mediated signaling in SMCs links elastin deficiency and pathological stenosis, and inhibiting this pathway is an attractive therapeutic strategy for SVAS.

PMID:
26858344
PMCID:
PMC4813675
DOI:
10.1084/jem.20150688
[Indexed for MEDLINE]
Free PMC Article
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