Mural cell dysfunction contributes to diastolic heart failure by promoting endothelial dysfunction and vessel remodelling
Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular disease associated with metabolic comorbidities. Microvascular dysfunction has been proposed to drive HFpEF, likely via endothelial cell (EC) dysfunction, yet the role of the mural cells herein has...
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BMC
2025-02-01
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| Series: | Cardiovascular Diabetology |
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| Online Access: | https://doi.org/10.1186/s12933-025-02623-w |
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| author | Mandy O. J. Grootaert Alessandra Pasut Jana Raman Steven J. Simmonds Bram Callewaert Ümare Col Mieke Dewerchin Peter Carmeliet Stephane Heymans Elizabeth A. V. Jones |
| author_facet | Mandy O. J. Grootaert Alessandra Pasut Jana Raman Steven J. Simmonds Bram Callewaert Ümare Col Mieke Dewerchin Peter Carmeliet Stephane Heymans Elizabeth A. V. Jones |
| author_sort | Mandy O. J. Grootaert |
| collection | DOAJ |
| description | Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular disease associated with metabolic comorbidities. Microvascular dysfunction has been proposed to drive HFpEF, likely via endothelial cell (EC) dysfunction, yet the role of the mural cells herein has never been explored. Methods We used the diabetic db/db mouse given 1% salt as a new model of HFpEF and crossed then with PDGFRβtg/tg-CreERT2-EYFPtg/tg mice to label the mural cells. We combined single-cell RNA sequencing, NichetNet analysis and histology to determine the role of mural cell dysfunction in HFpEF. Results Db/db mice given 1% salt for 8 weeks developed diastolic dysfunction preceded by capillary density loss, pericyte loss and vessel regression. At 4 weeks of salt, hearts of db/db mice already showed EC dysfunction associated with an anti-angiogenic signature, and an increase in pericyte-EC intracellular space. Db/db + salt hearts were further characterised by increased ACTA2 expression, arteriole wall thickening and vessel enlargement. NicheNet analysis on the single cell transcriptomic data revealed little signalling from the ECs to the mural cells; instead, mural cells signalled strongly to ECs. Mechanistically, pericyte dysfunction induces an EC growth arrest via TNFα-dependent paracrine signalling and downstream signalling through STAT1. Conclusion Mural cell dysfunction contributes to HFpEF by inducing coronary vessel remodelling, at least in part by reducing EC proliferation and inducing EC inflammation through TNFα-dependent paracrine signalling. Graphic abstract |
| format | Article |
| id | doaj-art-c8090c6f2cf9442c8a6b36581e9baeb7 |
| institution | Kabale University |
| issn | 1475-2840 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj-art-c8090c6f2cf9442c8a6b36581e9baeb72025-02-09T12:10:53ZengBMCCardiovascular Diabetology1475-28402025-02-0124111610.1186/s12933-025-02623-wMural cell dysfunction contributes to diastolic heart failure by promoting endothelial dysfunction and vessel remodellingMandy O. J. Grootaert0Alessandra Pasut1Jana Raman2Steven J. Simmonds3Bram Callewaert4Ümare Col5Mieke Dewerchin6Peter Carmeliet7Stephane Heymans8Elizabeth A. V. Jones9Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU LeuvenLaboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology (CCB), KU LeuvenCentre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU LeuvenCentre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU LeuvenCentre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU LeuvenCentre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU LeuvenLaboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology (CCB), KU LeuvenLaboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology (CCB), KU LeuvenCentre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU LeuvenCentre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU LeuvenAbstract Background Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular disease associated with metabolic comorbidities. Microvascular dysfunction has been proposed to drive HFpEF, likely via endothelial cell (EC) dysfunction, yet the role of the mural cells herein has never been explored. Methods We used the diabetic db/db mouse given 1% salt as a new model of HFpEF and crossed then with PDGFRβtg/tg-CreERT2-EYFPtg/tg mice to label the mural cells. We combined single-cell RNA sequencing, NichetNet analysis and histology to determine the role of mural cell dysfunction in HFpEF. Results Db/db mice given 1% salt for 8 weeks developed diastolic dysfunction preceded by capillary density loss, pericyte loss and vessel regression. At 4 weeks of salt, hearts of db/db mice already showed EC dysfunction associated with an anti-angiogenic signature, and an increase in pericyte-EC intracellular space. Db/db + salt hearts were further characterised by increased ACTA2 expression, arteriole wall thickening and vessel enlargement. NicheNet analysis on the single cell transcriptomic data revealed little signalling from the ECs to the mural cells; instead, mural cells signalled strongly to ECs. Mechanistically, pericyte dysfunction induces an EC growth arrest via TNFα-dependent paracrine signalling and downstream signalling through STAT1. Conclusion Mural cell dysfunction contributes to HFpEF by inducing coronary vessel remodelling, at least in part by reducing EC proliferation and inducing EC inflammation through TNFα-dependent paracrine signalling. Graphic abstracthttps://doi.org/10.1186/s12933-025-02623-wPericytesSmooth muscle cellsEndothelial cellsHFpEFDiastolic dysfunction |
| spellingShingle | Mandy O. J. Grootaert Alessandra Pasut Jana Raman Steven J. Simmonds Bram Callewaert Ümare Col Mieke Dewerchin Peter Carmeliet Stephane Heymans Elizabeth A. V. Jones Mural cell dysfunction contributes to diastolic heart failure by promoting endothelial dysfunction and vessel remodelling Cardiovascular Diabetology Pericytes Smooth muscle cells Endothelial cells HFpEF Diastolic dysfunction |
| title | Mural cell dysfunction contributes to diastolic heart failure by promoting endothelial dysfunction and vessel remodelling |
| title_full | Mural cell dysfunction contributes to diastolic heart failure by promoting endothelial dysfunction and vessel remodelling |
| title_fullStr | Mural cell dysfunction contributes to diastolic heart failure by promoting endothelial dysfunction and vessel remodelling |
| title_full_unstemmed | Mural cell dysfunction contributes to diastolic heart failure by promoting endothelial dysfunction and vessel remodelling |
| title_short | Mural cell dysfunction contributes to diastolic heart failure by promoting endothelial dysfunction and vessel remodelling |
| title_sort | mural cell dysfunction contributes to diastolic heart failure by promoting endothelial dysfunction and vessel remodelling |
| topic | Pericytes Smooth muscle cells Endothelial cells HFpEF Diastolic dysfunction |
| url | https://doi.org/10.1186/s12933-025-02623-w |
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