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Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
Microfibril Denudation Marks Early Aortic Vulnerability in SMAD3 Variant Carriers: A Multigenerational Study.
Paulina M Kowalewska1, Hao Yin1, Mofei Wang1,2
1Robarts Research Institute, The University of Western Ontario, London, Canada. (P.M.K., H.Y., M.W., B.B., S.H., J.P.S., K.Y.F., Z.N., C.O.N., M.T.J.H., J.L., R.A.H., J.G.P.).
Arteriosclerosis, Thrombosis, and Vascular Biology
|June 11, 2026
Summary
Loeys-Dietz syndrome 3 involves a SMAD3 variant, leading to aortic dissection risk. A novel SMAD3-PRRX2-microfibril pathway disruption explains smooth muscle cell detachment and heightened aortic disease risk.
Area of Science:
- Cardiovascular Biology
- Genetics
- Connective Tissue Disorders
Background:
- Loeys-Dietz syndrome 3 (LDS3) patients face thoracic aortic dissection risk, even without significant aortic dilation.
- A pathogenic SMAD3 variant is a known genetic trigger, but the underlying cellular mechanisms of aortic risk are unclear.
Purpose of the Study:
- To investigate the cardiovascular profile and cellular mechanisms of aortic disease in individuals with a SMAD3 missense variant.
- To identify the molecular pathways contributing to thoracic aortopathy in LDS3.
Main Methods:
- Cardiovascular phenotyping of 57 individuals from a 4-generation family with a SMAD3 variant (p.Arg287Gln).
- Quantification of aortic medial architecture and elastin-microfibril network using 2D/3D profiling.
- Investigation of TGFß-dependent networks via RNA sequencing of smooth muscle cells (SMCs) and ChIP.
Main Results:
- Family members exhibited thoracic aortopathy, peripheral aneurysms, cerebrovascular disease, and mitral valve prolapse, with a median age of 36.5 years for the first aortic event.
- Early aortic pathology showed SMCs detaching from elastic lamellae, with poorly decorated elastic fibers and reduced microfibril components.
- A SMAD3-PRRX2-microfibril axis was identified; PRRX2 downregulation in LDS3 SMCs correlated with reduced microfibril expression, and SMAD3 overexpression restored both.
Conclusions:
- SMCs detaching from unsheathed elastic fibers represent an early pathological process in LDS3 aortas.
- A disrupted SMAD3-PRRX2-microfibril axis contributes to SMC disconnection and increased aortic risk in LDS3.
