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

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.