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Biomechanical and transcriptional evidence that smooth muscle cell death drives an osteochondrogenic phenotype and severe proximal vascular disease in progeria

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Abstract

Hutchinson–Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end-of-life. We found a progressive disease process in proximal elastic arteries that was less evident in distal muscular arteries. Changes in aortic structure and function were then associated with changes in transcriptomics assessed via both bulk and single cell RNA sequencing, which suggested a novel sequence of progressive aortic disease: adverse extracellular matrix remodeling followed by mechanical stress-induced smooth muscle cell death, leading a subset of remnant smooth muscle cells to an osteochondrogenic phenotype that results in an accumulation of proteoglycans that thickens the aortic wall and increases pulse wave velocity, with late calcification exacerbating these effects. Increased central artery pulse wave velocity is known to drive left ventricular diastolic dysfunction, the primary diagnosis in progeria children. It appears that mechanical stresses above ~ 80 kPa initiate this progressive aortic disease process, explaining why elastic lamellar structures that are organized early in development under low wall stresses appear to be nearly normal whereas other medial constituents worsen progressively in adulthood. Mitigating early mechanical stress-driven smooth muscle cell loss/phenotypic modulation promises to have important cardiovascular implications in progeria patients.

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All data needed to evaluate the conclusions of the paper are in the paper and the Supplementary Materials. Additional information is available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by a grant from the US NIH (R01 HL105297, JDH) and the Masason Foundation (YK).

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Author notes

  1. Sae-Il Murtada and Yuki Kawamura have contributed equally.

Authors and Affiliations

  1. Department of Biomedical Engineering, Yale University, New Haven, CT, USA

    Sae-Il Murtada, Cristina Cavinato, Abhay B. Ramachandra, Bart Spronck, David S. Li & Jay D. Humphrey

  2. Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA

    Yuki Kawamura

  3. Department of Surgery, Yale School of Medicine, New Haven, CT, USA

    Molly Wang & George Tellides

  4. Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA

    George Tellides & Jay D. Humphrey

  5. Department of Biomedical Engineering, Maastricht University, Maastricht, Netherlands

    Bart Spronck

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  1. Sae-Il Murtada
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Contributions

Design of the project was contributed by SIM, YK, GT, JDH; Data collection was contributed by SIM, YK, CC, MW, ABR, BS; Data analysis and interpretation were contributed by SIM, YK, CC, DSL, GT, JDH. Writing and editing were contributed by SIM, YK, CC, GT, JDH.

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Correspondence to Jay D. Humphrey.

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All live animal procedures were conducted in accordance with Federal Regulations and were approved by the Yale Institutional Animal Care and Use Committee prior to beginning the work.

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Murtada, SI., Kawamura, Y., Cavinato, C. et al. Biomechanical and transcriptional evidence that smooth muscle cell death drives an osteochondrogenic phenotype and severe proximal vascular disease in progeria. Biomech Model Mechanobiol 22, 1333–1347 (2023). https://doi.org/10.1007/s10237-023-01722-5

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