SMC Abca1 and Abcg1 Deficiency Enhances Urinary Bladder Distension but Not Atherosclerosis
Authors: Halmos Benedek , La Rose Anouk M. , Methorst Daisey , Groenen Anouk G. , Nakládal Dalibor , Bazioti Venetia , Koster Mirjam H. , Kloosterhuis Niels J. , Buiten Azuwerus van , Schouten Elisabeth M. , Huijkman Nicolette C.A. , Langelaar-Makkinje Miriam , Bongiovanni Laura , De Neck Simon M. , de Bruin Alain , Buikema Hendrik , Deelman Leo E. , van den Heuvel Marius C. , Kuipers Folkert , de Jong Igle Jan , Sluimer Judith C. , Jørgensen Helle F. , Henning Robert H. , Westerterp Marit 
Published: February 2025

BACKGROUND:

Smooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by α-ARs (α-adrenergic receptors). Plasma membrane cholesterol accumulation affects α
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 α
1
-AR agonist phenylephrine. Unexpectedly,
SMC-Abca1/Abcg1
deficiency induced urinary bladder distension by >20-fold. This was reversed by the α
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 α
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.