Yogendran, Vaishaali;
Mele, Laura;
Prysyazhna, Oleksandra;
Budhram-Mahadeo, Vishwanie S;
(2023)
Vascular dysfunction caused by loss of Brn-3b/POU4F2 transcription factor in aortic vascular smooth muscle cells is linked to deregulation of calcium signalling pathways.
Cell Death & Disease
, 14
(11)
, Article 770. 10.1038/s41419-023-06306-w.
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Abstract
Phenotypic and functional changes in vascular smooth muscle cells (VSMCs) contribute significantly to cardiovascular diseases (CVD) but factors driving early adverse vascular changes are poorly understood. We report on novel and important roles for the Brn-3b/POU4F2 (Brn-3b) transcription factor (TF) in controlling VSMC integrity and function. Brn-3b protein is expressed in mouse aorta with localisation to VSMCs. Male Brn-3b knock-out (KO) aortas displayed extensive remodelling with increased extracellular matrix (ECM) deposition, elastin fibre disruption and small but consistent narrowing/coarctation in the descending aortas. RNA sequencing analysis showed that these effects were linked to deregulation of genes required for calcium (Ca2+) signalling, vascular contractility, sarco-endoplasmic reticulum (S/ER) stress responses and immune function in Brn-3b KO aortas and validation studies confirmed changes in Ca2+ signalling genes linked to increased intracellular Ca2+ and S/ER Ca2+ depletion [e.g. increased, Cacna1d Ca2+ channels; ryanodine receptor 2, (RyR2) and phospholamban (PLN) but reduced ATP2a1, encoding SERCA1 pump] and chaperone proteins, Hspb1, HspA8, DnaJa1 linked to increased S/ER stress, which also contributes to contractile dysfunction. Accordingly, vascular rings from Brn-3b KO aortas displayed attenuated contractility in response to KCl or phenylephrine (PE) while Brn-3b KO-derived VSMC displayed abnormal Ca2+ signalling following ATP stimulation. This data suggests that Brn-3b target genes are necessary to maintain vascular integrity /contractile function and deregulation upon loss of Brn-3b will contribute to contractile dysfunction linked to CVD.
| Type: | Article |
|---|---|
| Title: | Vascular dysfunction caused by loss of Brn-3b/POU4F2 transcription factor in aortic vascular smooth muscle cells is linked to deregulation of calcium signalling pathways |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41419-023-06306-w |
| Publisher version: | https://doi.org/10.1038/s41419-023-06306-w |
| Language: | English |
| Additional information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Mice, Male, Animals, Muscle, Smooth, Vascular, Calcium, Transcription Factor Brn-3B, Aorta, Cardiovascular Diseases, Myocytes, Smooth Muscle |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10182527 |
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