Urogenital alterations in aged male caveolin-1 knockout mice.
OBJECTIVE
Caveolae are flask-shaped invaginations of the plasma membrane formed by the oligomerization of caveolins. Because only smooth muscle contains all caveolin (Cav) family members (Cav-1, 2 and 3), we examined the contribution of each caveolin to urogenital smooth muscle structure/function.


METHODS
WT, Cav-1, 2, 3 and -1/3 knockout (KO) mouse bladders were characterized by Western blot, co-immunoprecipitation, immunofluorescence microscopy, electron microscopy, histochemistry and pharmacological techniques. Cystometric analysis was performed in conscious, freely moving mice. Other urogenital organs were investigated by histological analysis.


RESULTS
The loss of bladder Cav-1 results in a marked decrease in Cav-2 but not Cav-3 expression. Ablation of Cav-3 fails to alter Cav-1 or Cav-2 expression. Deletion of Cav-1 results in the almost complete loss of caveolae, while Cav-2 KO and Cav-3 KO mouse smooth muscle showed a normal number of caveolae. The loss of Cav-1 generated caveolae led to significant urogenital changes in male mice (most marked by 12 months of age), namely 1) bladder weight-to-body weight ratios were increased, 2) the bladder smooth muscle layer was thickened, 3) the bladders had increased baseline, threshold and spontaneous pressures, 4) bladder strips showed a decreased contractile response to carbachol and KCl, and 5) these smooth muscle changes were accompanied by marked fluid accumulation in the prostate and seminal vesicles, with intracellular vacuolization in the kidneys. As such, male Cav-1 KO mice may be a useful animal model for studying LUTD (lower urinary tract dysfunction) that is so prevalent in aging male patients.


CONCLUSIONS
The loss of Cav-1 and, thus, of most smooth muscle cell caveolae results in significant bladder dysfunction and urogenital organ changes in aged male mice.
Woodman
Scott E
SE
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Cheung
Michelle W-C
MW
Tarr
Moses
M
North
Amanda C
AC
Schubert
William
W
Lagaud
Guy
G
Marks
Carolyn B
CB
Russell
Robert G
RG
Hassan
Ghada S
GS
Factor
Stephen M
SM
Christ
George J
GJ
Lisanti
Michael P
MP
D000818:Animals; D051242:Caveolin 1; D022461:Caveolins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology*; D014566:Urogenital System / Q000166:cytology*
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins