SMC Abca1 and Abcg1 Deficiency Enhances Urinary Bladder Distension but Not Atherosclerosis

Benedek Halmos; Anouk M La Rose; Daisey Methorst; Anouk G Groenen; Dalibor Nakládal; Venetia Bazioti; Mirjam H Koster; Niels J Kloosterhuis; Azuwerus van Buiten; Elisabeth M Schouten; Nicolette C A Huijkman; Miriam Langelaar-Makkinje; Laura Bongiovanni; Simon M De Neck; Alain de Bruin; Hendrik Buikema; Leo E Deelman; Marius C van den Heuvel; Folkert Kuipers; Igle Jan de Jong; Judith C Sluimer; Helle F Jørgensen; Robert H Henning; Marit Westerterp

doi:10.1161/CIRCRESAHA.124.325103

SMC Abca1 and Abcg1 Deficiency Enhances Urinary Bladder Distension but Not Atherosclerosis

Benedek Halmos, Anouk M La Rose, Daisey Methorst, Anouk G Groenen, Dalibor Nakládal, Venetia Bazioti, Mirjam H Koster, Niels J Kloosterhuis, Azuwerus van Buiten, Elisabeth M Schouten, Nicolette C A Huijkman, Miriam Langelaar-Makkinje, Laura Bongiovanni, Simon M De Neck, Alain de Bruin, Hendrik Buikema, Leo E Deelman, Marius C van den Heuvel, Folkert Kuipers, Igle Jan de JongJudith C Sluimer, Helle F Jørgensen, Robert H Henning, Marit Westerterp^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Smooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by α-ARs (α-adrenergic receptors). Plasma membrane cholesterol accumulation affects α 1-AR signaling and promotes loss of SMC contractile markers in vitro. ABCA1 and ABCG1 (ATP-binding cassette transporter A1 and G1) mediate cholesterol efflux to HDL (high-density lipoprotein). ABCA1/ABCG1 show high expression in medial and low expression in intimal SMCs of atherosclerotic plaques. The role of ABCA1 and ABCG1 in SMC-mediated vasoconstriction and atherogenesis remains poorly understood.

METHODS: We generated mice with SMC-specific Abca1/Abcg1 deficiency on the low-density lipoprotein receptor-deficient ( Ldlr - / - ) background by crossbreeding Abca1 fl/fl Abcg1 fl/fl Ldlr -/- mice with Myh11Cre ERT2 transgenic mice. To induce SMC cholesterol accumulation and atherogenesis, we fed Myh11Cre ERT2 Abca1 fl/fl Abcg1 fl/fl Ldlr -/- , Myh11Cre ERT2 Abca1 fl/fl Ldlr -/- , Myh11Cre ERT2 Abcg1 fl/fl Ldlr -/- , and Myh11Cre ERT2 Ldlr -/- mice Western-type diet for 16 weeks.

RESULTS: Combined SMC-Abca1/Abcg1 deficiency increased vasoconstriction in aortic rings induced by the α 1-AR agonist phenylephrine. Unexpectedly, SMC- Abca1/Abcg1 deficiency induced urinary bladder distension by >20-fold. This was reversed by the α 1-AR antagonist tamsulosin, indicating its dependence on bladder neck SMC constriction. Moreover, SMC- Abca1/Abcg1 deficiency decreased contractile markers and increased macrophage and fibroblast markers in bladder SMCs, indicating SMC transdifferentiation. This was accompanied by free cholesterol accumulation and increased endoplasmic reticulum stress. SMC- Abca1/Abcg1 deficiency did not induce thoracic aorta SMC transdifferentiation, presumably due to increased cholesteryl ester accumulation and no endoplasmic reticulum stress in thoracic aorta SMCs. Surprisingly, SMC- Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size or composition in the aortic root or brachiocephalic artery.

CONCLUSIONS: We uncover a new role of SMC cholesterol efflux pathways in suppressing α 1-AR-mediated vasoconstriction and bladder SMC transdifferentiation, decreasing urinary bladder distension. Our data may provide a mechanistic link for the association between urinary bladder distension and diabetes in humans, particularly because diabetes is associated with decreased cholesterol efflux. SMC- Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size or plaque composition, presumably due to low expression of Abca1/Abcg1 in intimal SMCs.

Original language	English
Pages (from-to)	491-507
Number of pages	17
Journal	Circulation Research
Volume	136
Issue number	5
Early online date	11 Feb 2025
DOIs	https://doi.org/10.1161/CIRCRESAHA.124.325103
Publication status	Published - 28 Feb 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors.

Funding

This work was supported by Marie Sk\u0142odowska-Curie grant 945478 from European Union (EU) Horizon 2020, the Slovak Academic and Scientific Programme grant 3333/03/02, and the Slovak Research and Development Agency grant PP-MSCA-2022-0001 (support for projects Marie Sk\u0142odowska-Curie Actions-2022-0001) (to D. Nakl\u00E1dal); VIDI grant 917.15.350 and an Aspasia grant from the Netherlands Organization of Scientific Research and a Rosalind Franklin Fellowship with an EU Co-Fund attached from the University of Groningen (to M. Westerterp); and the British Heart Foundation \u2014 German Centre for Cardiovascular Research \u2014Dutch Heart Foundation International Cardiovascular Research Partnership Award 02-001-2022-0125 (acronym PLAK TALK) to H.F. J\u00F8rgensen and M. Westerterp.

Funders	Funder number
Deutsches Zentrum für Herz-Kreislaufforschung
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Rijksuniversiteit Groningen
British Heart Foundation
European Commission	3333/03/02
Agentúra na Podporu Výskumu a Vývoja	PP-MSCA-2022-0001
Dutch Heart Foundation International Cardiovascular Research	02-001-2022-0125
H2020 Marie Skłodowska-Curie Actions	945478
Marie Skłodowska-Curie Actions-2022-0001	917.15.350

Keywords

atherosclerosis
cell transdifferentiation
cholesterol
myocytes, smooth muscle
vasoconstriction

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Halmos, B., La Rose, A. M., Methorst, D., Groenen, A. G., Nakládal, D., Bazioti, V., Koster, M. H., Kloosterhuis, N. J., Buiten, A. V., Schouten, E. M., Huijkman, N. C. A., Langelaar-Makkinje, M., Bongiovanni, L., De Neck, S. M., de Bruin, A., Buikema, H., Deelman, L. E., van den Heuvel, M. C., Kuipers, F., ... Westerterp, M. (2025). SMC Abca1 and Abcg1 Deficiency Enhances Urinary Bladder Distension but Not Atherosclerosis. Circulation Research, 136(5), 491-507. https://doi.org/10.1161/CIRCRESAHA.124.325103

@article{b0c6ebb96b5e44cc97c8b6aa35f1565a,

title = "SMC Abca1 and Abcg1 Deficiency Enhances Urinary Bladder Distension but Not Atherosclerosis",

abstract = "BACKGROUND: Smooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by α-ARs (α-adrenergic receptors). Plasma membrane cholesterol accumulation affects α 1-AR signaling and promotes loss of SMC contractile markers in vitro. ABCA1 and ABCG1 (ATP-binding cassette transporter A1 and G1) mediate cholesterol efflux to HDL (high-density lipoprotein). ABCA1/ABCG1 show high expression in medial and low expression in intimal SMCs of atherosclerotic plaques. The role of ABCA1 and ABCG1 in SMC-mediated vasoconstriction and atherogenesis remains poorly understood. METHODS: We generated mice with SMC-specific Abca1/Abcg1 deficiency on the low-density lipoprotein receptor-deficient ( Ldlr - / - ) background by crossbreeding Abca1 fl/fl Abcg1 fl/fl Ldlr -/- mice with Myh11Cre ERT2 transgenic mice. To induce SMC cholesterol accumulation and atherogenesis, we fed Myh11Cre ERT2 Abca1 fl/fl Abcg1 fl/fl Ldlr -/- , Myh11Cre ERT2 Abca1 fl/fl Ldlr -/- , Myh11Cre ERT2 Abcg1 fl/fl Ldlr -/- , and Myh11Cre ERT2 Ldlr -/- mice Western-type diet for 16 weeks. RESULTS: Combined SMC-Abca1/Abcg1 deficiency increased vasoconstriction in aortic rings induced by the α 1-AR agonist phenylephrine. Unexpectedly, SMC- Abca1/Abcg1 deficiency induced urinary bladder distension by >20-fold. This was reversed by the α 1-AR antagonist tamsulosin, indicating its dependence on bladder neck SMC constriction. Moreover, SMC- Abca1/Abcg1 deficiency decreased contractile markers and increased macrophage and fibroblast markers in bladder SMCs, indicating SMC transdifferentiation. This was accompanied by free cholesterol accumulation and increased endoplasmic reticulum stress. SMC- Abca1/Abcg1 deficiency did not induce thoracic aorta SMC transdifferentiation, presumably due to increased cholesteryl ester accumulation and no endoplasmic reticulum stress in thoracic aorta SMCs. Surprisingly, SMC- Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size or composition in the aortic root or brachiocephalic artery. CONCLUSIONS: We uncover a new role of SMC cholesterol efflux pathways in suppressing α 1-AR-mediated vasoconstriction and bladder SMC transdifferentiation, decreasing urinary bladder distension. Our data may provide a mechanistic link for the association between urinary bladder distension and diabetes in humans, particularly because diabetes is associated with decreased cholesterol efflux. SMC- Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size or plaque composition, presumably due to low expression of Abca1/Abcg1 in intimal SMCs. ",

keywords = "atherosclerosis, cell transdifferentiation, cholesterol, myocytes, smooth muscle, vasoconstriction",

author = "Benedek Halmos and {La Rose}, {Anouk M} and Daisey Methorst and Groenen, {Anouk G} and Dalibor Nakl{\'a}dal and Venetia Bazioti and Koster, {Mirjam H} and Kloosterhuis, {Niels J} and Buiten, {Azuwerus van} and Schouten, {Elisabeth M} and Huijkman, {Nicolette C A} and Miriam Langelaar-Makkinje and Laura Bongiovanni and {De Neck}, {Simon M} and {de Bruin}, Alain and Hendrik Buikema and Deelman, {Leo E} and {van den Heuvel}, {Marius C} and Folkert Kuipers and {de Jong}, {Igle Jan} and Sluimer, {Judith C} and J{\o}rgensen, {Helle F} and Henning, {Robert H} and Marit Westerterp",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors.",

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month = feb,

day = "28",

doi = "10.1161/CIRCRESAHA.124.325103",

language = "English",

volume = "136",

pages = "491--507",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "Lippincott Williams and Wilkins",

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Halmos, B, La Rose, AM, Methorst, D, Groenen, AG, Nakládal, D, Bazioti, V, Koster, MH, Kloosterhuis, NJ, Buiten, AV, Schouten, EM, Huijkman, NCA, Langelaar-Makkinje, M, Bongiovanni, L, De Neck, SM, de Bruin, A, Buikema, H, Deelman, LE, van den Heuvel, MC, Kuipers, F, de Jong, IJ, Sluimer, JC, Jørgensen, HF, Henning, RH & Westerterp, M 2025, 'SMC Abca1 and Abcg1 Deficiency Enhances Urinary Bladder Distension but Not Atherosclerosis', Circulation Research, vol. 136, no. 5, pp. 491-507. https://doi.org/10.1161/CIRCRESAHA.124.325103

TY - JOUR

T1 - SMC Abca1 and Abcg1 Deficiency Enhances Urinary Bladder Distension but Not Atherosclerosis

AU - Halmos, Benedek

AU - La Rose, Anouk M

AU - Methorst, Daisey

AU - Groenen, Anouk G

AU - Nakládal, Dalibor

AU - Bazioti, Venetia

AU - Koster, Mirjam H

AU - Kloosterhuis, Niels J

AU - Buiten, Azuwerus van

AU - Schouten, Elisabeth M

AU - Huijkman, Nicolette C A

AU - Langelaar-Makkinje, Miriam

AU - Bongiovanni, Laura

AU - De Neck, Simon M

AU - de Bruin, Alain

AU - Buikema, Hendrik

AU - Deelman, Leo E

AU - van den Heuvel, Marius C

AU - Kuipers, Folkert

AU - de Jong, Igle Jan

AU - Sluimer, Judith C

AU - Jørgensen, Helle F

AU - Henning, Robert H

AU - Westerterp, Marit

PY - 2025/2/28

Y1 - 2025/2/28

N2 - BACKGROUND: Smooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by α-ARs (α-adrenergic receptors). Plasma membrane cholesterol accumulation affects α 1-AR signaling and promotes loss of SMC contractile markers in vitro. ABCA1 and ABCG1 (ATP-binding cassette transporter A1 and G1) mediate cholesterol efflux to HDL (high-density lipoprotein). ABCA1/ABCG1 show high expression in medial and low expression in intimal SMCs of atherosclerotic plaques. The role of ABCA1 and ABCG1 in SMC-mediated vasoconstriction and atherogenesis remains poorly understood. METHODS: We generated mice with SMC-specific Abca1/Abcg1 deficiency on the low-density lipoprotein receptor-deficient ( Ldlr - / - ) background by crossbreeding Abca1 fl/fl Abcg1 fl/fl Ldlr -/- mice with Myh11Cre ERT2 transgenic mice. To induce SMC cholesterol accumulation and atherogenesis, we fed Myh11Cre ERT2 Abca1 fl/fl Abcg1 fl/fl Ldlr -/- , Myh11Cre ERT2 Abca1 fl/fl Ldlr -/- , Myh11Cre ERT2 Abcg1 fl/fl Ldlr -/- , and Myh11Cre ERT2 Ldlr -/- mice Western-type diet for 16 weeks. RESULTS: Combined SMC-Abca1/Abcg1 deficiency increased vasoconstriction in aortic rings induced by the α 1-AR agonist phenylephrine. Unexpectedly, SMC- Abca1/Abcg1 deficiency induced urinary bladder distension by >20-fold. This was reversed by the α 1-AR antagonist tamsulosin, indicating its dependence on bladder neck SMC constriction. Moreover, SMC- Abca1/Abcg1 deficiency decreased contractile markers and increased macrophage and fibroblast markers in bladder SMCs, indicating SMC transdifferentiation. This was accompanied by free cholesterol accumulation and increased endoplasmic reticulum stress. SMC- Abca1/Abcg1 deficiency did not induce thoracic aorta SMC transdifferentiation, presumably due to increased cholesteryl ester accumulation and no endoplasmic reticulum stress in thoracic aorta SMCs. Surprisingly, SMC- Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size or composition in the aortic root or brachiocephalic artery. CONCLUSIONS: We uncover a new role of SMC cholesterol efflux pathways in suppressing α 1-AR-mediated vasoconstriction and bladder SMC transdifferentiation, decreasing urinary bladder distension. Our data may provide a mechanistic link for the association between urinary bladder distension and diabetes in humans, particularly because diabetes is associated with decreased cholesterol efflux. SMC- Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size or plaque composition, presumably due to low expression of Abca1/Abcg1 in intimal SMCs.

AB - BACKGROUND: Smooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by α-ARs (α-adrenergic receptors). Plasma membrane cholesterol accumulation affects α 1-AR signaling and promotes loss of SMC contractile markers in vitro. ABCA1 and ABCG1 (ATP-binding cassette transporter A1 and G1) mediate cholesterol efflux to HDL (high-density lipoprotein). ABCA1/ABCG1 show high expression in medial and low expression in intimal SMCs of atherosclerotic plaques. The role of ABCA1 and ABCG1 in SMC-mediated vasoconstriction and atherogenesis remains poorly understood. METHODS: We generated mice with SMC-specific Abca1/Abcg1 deficiency on the low-density lipoprotein receptor-deficient ( Ldlr - / - ) background by crossbreeding Abca1 fl/fl Abcg1 fl/fl Ldlr -/- mice with Myh11Cre ERT2 transgenic mice. To induce SMC cholesterol accumulation and atherogenesis, we fed Myh11Cre ERT2 Abca1 fl/fl Abcg1 fl/fl Ldlr -/- , Myh11Cre ERT2 Abca1 fl/fl Ldlr -/- , Myh11Cre ERT2 Abcg1 fl/fl Ldlr -/- , and Myh11Cre ERT2 Ldlr -/- mice Western-type diet for 16 weeks. RESULTS: Combined SMC-Abca1/Abcg1 deficiency increased vasoconstriction in aortic rings induced by the α 1-AR agonist phenylephrine. Unexpectedly, SMC- Abca1/Abcg1 deficiency induced urinary bladder distension by >20-fold. This was reversed by the α 1-AR antagonist tamsulosin, indicating its dependence on bladder neck SMC constriction. Moreover, SMC- Abca1/Abcg1 deficiency decreased contractile markers and increased macrophage and fibroblast markers in bladder SMCs, indicating SMC transdifferentiation. This was accompanied by free cholesterol accumulation and increased endoplasmic reticulum stress. SMC- Abca1/Abcg1 deficiency did not induce thoracic aorta SMC transdifferentiation, presumably due to increased cholesteryl ester accumulation and no endoplasmic reticulum stress in thoracic aorta SMCs. Surprisingly, SMC- Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size or composition in the aortic root or brachiocephalic artery. CONCLUSIONS: We uncover a new role of SMC cholesterol efflux pathways in suppressing α 1-AR-mediated vasoconstriction and bladder SMC transdifferentiation, decreasing urinary bladder distension. Our data may provide a mechanistic link for the association between urinary bladder distension and diabetes in humans, particularly because diabetes is associated with decreased cholesterol efflux. SMC- Abca1/Abcg1 deficiency did not affect atherosclerotic lesion size or plaque composition, presumably due to low expression of Abca1/Abcg1 in intimal SMCs.

KW - atherosclerosis

KW - cell transdifferentiation

KW - cholesterol

KW - myocytes, smooth muscle

KW - vasoconstriction

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U2 - 10.1161/CIRCRESAHA.124.325103

DO - 10.1161/CIRCRESAHA.124.325103

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C2 - 39931819

SN - 0009-7330

VL - 136

SP - 491

EP - 507

JO - Circulation Research

JF - Circulation Research

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ER -

SMC Abca1 and Abcg1 Deficiency Enhances Urinary Bladder Distension but Not Atherosclerosis

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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