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 α1-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 Abca1fl/flAbcg1fl/flLdlr-/- mice with Myh11CreERT2 transgenic mice. To induce SMC cholesterol accumulation and atherogenesis, we fed Myh11CreERT2Abca1fl/flAbcg1fl/flLdlr-/-, Myh11CreERT2Abca1fl/flLdlr-/-, Myh11CreERT2Abcg1fl/flLdlr-/-, and Myh11CreERT2Ldlr-/- mice Western-type diet for 16 weeks. RESULTS: Combined SMC-Abca1/Abcg1 deficiency increased vasoconstriction in aortic rings induced by the α1-AR agonist phenylephrine. Unexpectedly, SMC-Abca1/Abcg1 deficiency induced urinary bladder distension by >20-fold. This was reversed by the α1-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 α1-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 α1-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 Abca1fl/flAbcg1fl/flLdlr-/- mice with Myh11CreERT2 transgenic mice. To induce SMC cholesterol accumulation and atherogenesis, we fed Myh11CreERT2Abca1fl/flAbcg1fl/flLdlr-/-, Myh11CreERT2Abca1fl/flLdlr-/-, Myh11CreERT2Abcg1fl/flLdlr-/-, and Myh11CreERT2Ldlr-/- mice Western-type diet for 16 weeks. RESULTS: Combined SMC-Abca1/Abcg1 deficiency increased vasoconstriction in aortic rings induced by the α1-AR agonist phenylephrine. Unexpectedly, SMC-Abca1/Abcg1 deficiency induced urinary bladder distension by >20-fold. This was reversed by the α1-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 α1-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
U2 - 10.1161/CIRCRESAHA.124.325103
DO - 10.1161/CIRCRESAHA.124.325103
M3 - Article
SN - 0009-7330
VL - 136
SP - 491
EP - 507
JO - Circulation Research
JF - Circulation Research
IS - 5
ER -