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

Abstract

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. We generated mice with SMC-specific <i>Abca1/Abcg1</i> deficiency on the low-density lipoprotein receptor-deficient (<i>Ldlr</i>^<i>-</i>^<i>/</i>^<i>-</i>) background by crossbreeding <i>Abca1</i>^<i>fl/fl</i><i>Abcg1</i>^<i>fl/fl</i><i>Ldlr</i>^<i>-/-</i> mice with <i>Myh11Cre</i>^<i>ERT2</i> transgenic mice. To induce SMC cholesterol accumulation and atherogenesis, we fed <i>Myh11Cre</i>^<i>ERT2</i><i>Abca1</i>^<i>fl/fl</i><i>Abcg1</i>^<i>fl/fl</i><i>Ldlr</i>^<i>-/-</i>, <i>Myh11Cre</i>^<i>ERT2</i><i>Abca1</i>^<i>fl/fl</i><i>Ldlr</i>^<i>-/-</i>, <i>Myh11Cre</i>^<i>ERT2</i><i>Abcg1</i>^<i>fl/fl</i><i>Ldlr</i>^<i>-/-</i>, and <i>Myh11Cre</i>^<i>ERT2</i><i>Ldlr</i>^<i>-/-</i> mice Western-type diet for 16 weeks. Combined <i>SMC-Abca1/Abcg1</i> deficiency increased vasoconstriction in aortic rings induced by the α₁-AR agonist phenylephrine. Unexpectedly, <i>SMC-Abca1/Abcg1</i> 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, <i>SMC-Abca1/Abcg1</i> 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. <i>SMC-Abca1/Abcg1</i> 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, <i>SMC-Abca1/Abcg1</i> deficiency did not affect atherosclerotic lesion size or composition in the aortic root or brachiocephalic artery. 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. <i>SMC-Abca1/Abcg1</i> deficiency did not affect atherosclerotic lesion size or plaque composition, presumably due to low expression of <i>Abca1/Abcg1</i> in intimal SMCs.