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Crosstalk of human coronary perivascular adipose-derived stem cells with vascular cells: role of tissue factor

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Abstract

The coronary perivascular adipose tissue (cPVAT) has been associated to the burden of cardiovascular risk factors and to the underlying vessel atherosclerotic plaque severity. Although the “outside to inside” hypothesis of PVAT-derived-adipokine regulation of vessel function is currently accepted, whether the resident mesenchymal stem cells (ASCs) in PVAT have a regulatory role on the underlying vascular arterial smooth muscle cells (VSMCs) is not known. Here, we investigated the interactions between resident PVAT-ASCs and VSMCs. ASCs were obtained from PVAT overlying the left anterior descending (LAD) coronary artery of hearts removed at heart transplant operations. PVAT was obtained both from patients with non-ischemic and ischemic heart disease as the cause of heart transplant. ASCs were isolated from PVAT, phenotypically characterized by flow cytometry, functionally tested for proliferation, and differentiation. Crosstalk between ASCs and VSMCs was investigated by co-culture studies. ASCs were detected in the adventitia of the LAD-PVAT showing differentiation capacity and angiogenic potential. ASCs obtained from PVAT of non-ischemic and ischemic hearts showed different tissue factor (TF) expression levels, different VSMCs recruitment capacity through the axis ERK1/2-ETS1 signaling and different angiogenic potential. Induced upregulation of TF in ASCs isolated from ischemic PVAT rescued their angiogenic capacity in subcutaneously implanted plugs in mice, whereas silencing TF in ASCs decreased the proangiogenic capacity of non-ischemic ASCs. The results indicate for the first time a novel mechanism of regulation of VSMCs by PVAT-ASCs in angiogenesis, mediated by TF expression in ASCs. Regulation of TF in ASCs may become a therapeutic intervention to increase cardiac protection.

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Data availability

The data presented in this study are available in this article (and Supplementary Materials).

Abbreviations

ASCs:

Adipose-derived stem cells

AT:

Adipose tissue

cPVAT:

Coronary perivascular adipose tissue

ECs:

Endothelial cells

LAD:

Left anterior descending

PVAT:

Perivascular adipose tissue

SVF:

Stromal vascular fraction

TF:

Tissue factor

VECMs:

Vascular endothelial cell markers

VSMCs:

Vascular smooth muscle cells

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Acknowledgements

We thank Olaya Garcia for her excellent technical assistance. We thank the Fundación de Investigación Cardiovascular and the Fundación Jesus Serra for their support.

Funding

This work was supported by the Plan Nacional Proyectos Investigación Desarrollo (PID2019-107160RB-I00 to L.B.); Red Española de Terapias Avanzadas (TERAV-RD21/0017/0013 to L.B.); Centro de Investigación Biomedica en Red Cardiovascular (CIBERCV-CB16/11/00411 to L.B.); and Instituto de Salud Carlos III (ISCIII) (PI20/01517 to G.A.), cofounded by Fondo Europeo de Desarrollo Regional (FEDER) “Una Manera de Hacer Europa.” We thank the Generalitat of Catalunya (Secretaria d'Universitats i Recerca, Departament d'Economia i Coneixement, 2021 SGR 01006) and the Fundación Investigación Cardiovascular Fundación Jesus Serra for their continuous support.

Author information

Author notes

  1. Maria Teresa Bejar

    Present address: Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Puddicombe Way, Cambridge, CB2 0AW, UK

  2. Gemma Arderiu and Maria Teresa Bejar have contributed equally.

Authors and Affiliations

  1. Cardiovascular-Program, Institut de Recerca Sant Pau, IIB-Sant Pau, Carrer Sant Quintí, 77-79, 08041, Barcelona, Spain

    Gemma Arderiu, Maria Teresa Bejar, Anna Civit-Urgell, Esther Peña & Lina Badimon

  2. Ciber CV, Instituto Carlos III, Madrid, Spain

    Gemma Arderiu, Esther Peña & Lina Badimon

  3. Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB), Barcelona, Spain

    Anna Civit-Urgell

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  1. Gemma Arderiu
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  3. Anna Civit-Urgell
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  4. Esther Peña
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  5. Lina Badimon
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Contributions

GA, MTB and LB conceived and designed the study; MTB acquired the samples; GA, MTB, AC-U and EP performed experimental work and analyzed the data; GA and MTB wrote the original draft and GA and LB revised and edited the manuscript; founding acquisition was performed by GA and LB. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Gemma Arderiu.

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The authors declare that they have no conflict of interest.

Additional information

Subject codes: Stem cells, Angiogenesis, ischemia, Basic Science Research, and Vascular Biology.

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Arderiu, G., Bejar, M.T., Civit-Urgell, A. et al. Crosstalk of human coronary perivascular adipose-derived stem cells with vascular cells: role of tissue factor. Basic Res Cardiol 119, 291–307 (2024). https://doi.org/10.1007/s00395-024-01037-1

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