Yogendran, Vaishaali;
Mele, Laura;
Prysyazhna, Oleksandra;
Ponticos, Markella;
Budhram-Mahadeo, Vishwanie;
(2023)
Vascular dysfunction caused by loss of Brn-3b/POU4F2 transcription factor in aortic vascular smooth muscle cells is linked to deregulation of calcium signaling pathways.
Research Square: Durham, NC, USA.
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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 KO aortas displayed extensive remodelling with increased extracellular matrix (ECM) deposition, elastin fiber disruption and aortic coarctation. RNA sequencing analysis showed that these effects were linked to deregulation of genes required for calcium (Ca2+) signaling, 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 and contractile function and deregulation upon loss of Brn-3b will contribute to contractile dysfunction and CVD.
| Type: | Working / discussion paper |
|---|---|
| Title: | Vascular dysfunction caused by loss of Brn-3b/POU4F2 transcription factor in aortic vascular smooth muscle cells is linked to deregulation of calcium signaling pathways |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.21203/rs.3.rs-2402366/v1 |
| Publisher version: | https://doi.org/10.21203/rs.3.rs-2402366/v1 |
| Language: | English |
| Additional information: | ©The Authors(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Brn-3b TF, knockout mice, VSMC, Sarco-endoplasmic reticulum, vascular contractility, SERCA, RyR, vascular dysfunction, immune responses. |
| 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/10167433 |
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