Background: Smooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by alpha-ARs (alpha-adrenergic receptors). Plasma membrane cholesterol accumulation affects alpha(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 alpha(1)-AR agonist phenylephrine. Unexpectedly, SMC-Abca1/Abcg1 deficiency induced urinary bladder distension by >20-fold. This was reversed by the alpha(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 alpha(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.
SMC Abca1 and Abcg1 Deficiency Enhances Urinary Bladder Distension but Not Atherosclerosis
Bongiovanni L.;
2025-01-01
Abstract
Background: Smooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by alpha-ARs (alpha-adrenergic receptors). Plasma membrane cholesterol accumulation affects alpha(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 alpha(1)-AR agonist phenylephrine. Unexpectedly, SMC-Abca1/Abcg1 deficiency induced urinary bladder distension by >20-fold. This was reversed by the alpha(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 alpha(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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
