Abstract 16831: Deficiency of Cholesterol Efflux Pathways in Smooth Muscle Cells Enhances Vasoconstriction but Does Not Affect Atherosclerosis

Abstract

Smooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by α-adrenergic receptors (α-ARs). Plasma membrane cholesterol may affect α 1 -AR signaling, but consequences for SMC-mediated vasoconstriction are unclear. Cholesterol loading promotes SMC to macrophage transition in vitro , which may enhance atherosclerotic plaque vulnerability. However, the role of ATP Binding Cassette A1 and G1 (ABCA1/G1)-cholesterol efflux pathways in SMC-mediated vasoconstriction and atherogenesis remains poorly understood. We generated mice with SMC-specific Abca1/g1 deficiency on the low-density lipoprotein receptor deficient ( Ldlr -/- ) background by crossbreeding Abca1 fl/fl Abcg1 fl/fl Ldlr -/- mice with Myh11-Cre ERT2 transgenic mice and feeding them tamoxifen-diet. To induce SMC cholesterol accumulation and atherogenesis, we fed Myh11-Cre ERT2 Abca1 fl/fl Abcg1 fl/fl Ldlr -/- and Myh11-Cre ERT2 Ldlr -/- mice Western-type diet (WTD) for 16 weeks. Combined SMC-Abca1/g1 deficiency increased vasoconstriction in aortic rings induced by the α 1 -AR agonist phenylephrine, with reversal by methyl-β-cyclodextrin, substantiating its cholesterol-dependency. Unexpectedly, SMC - Abca1/g1 deficiency induced urinary bladder enlargement by >20-fold, resembling bladder outlet obstruction (BOO). This was reversed by the α 1 -AR antagonist tamsulosin, indicating its dependence on SMC constriction. Moreover, SMC - Abca1/g1 deficiency decreased SMC markers and increased macrophage- and fibroblast-markers in the bladder wall, enhancing collagen deposition, consistent with SMC transdifferentiation. However, after 16 weeks WTD, SMC - Abca1/g1 deficiency did not affect atherosclerotic lesion size, fibrous cap thickness, necrotic core, collagen, or macrophage content, suggesting that SMCs in atherosclerotic plaques were not affected. This may be due to low Abca1/g1 expression in intimal SMCs. We uncover a new role of SMC cholesterol efflux pathways in suppressing α 1 -AR mediated vasoconstriction and bladder SMC transdifferentiation, decreasing BOO. Our data may provide a mechanistic link for the association between BOO and diabetes in humans, particularly because diabetes is associated with decreased cholesterol efflux.