Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis.
Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis.
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DOI：
10.1084/jem.20150688
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发表时间：
2016-03-07
期刊：
影响因子：
--
通讯作者：
Greif DM
中科院分区：
文献类型：
--
作者：
Misra A;Sheikh AQ;Kumar A;Luo J;Zhang J;Hinton RB;Smoot L;Kaplan P;Urban Z;Qyang Y;Tellides G;Greif DM
Misra et al. elucidate the origin of smooth muscle cells involved in supravalvular aortic stenosis and identify the integrin β3 pathway as a therapeutic target in this disease. 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.
