Attenuated RhoA/Rho-kinase signaling in penis of transgenic sickle cell mice.
OBJECTIVE
The Ras homolog gene family, member A (RhoA) and its main downstream effector, Rho-kinase (ROCK) are important in maintaining the penis in the flaccid state. The pathophysiology of sickle cell disease-associated priapism is not well defined. We hypothesized that the RhoA/ROCK vasoconstrictive pathways might be involved in the development of priapism. Therefore, the objective of the present study was to evaluate the molecular changes in RhoA and ROCK in an established transgenic sickle cell mouse model of priapism.


METHODS
Two groups of mice were used: wild type (WT; C57BL/6) mice and transgenic sickle cell mice. We evaluated RhoA guanosine triphosphatase and total ROCK activities, as well as ROCK1 and ROCK2 protein expression, in WT and sickle mice penises. We also evaluated the in vivo erectile responses to cavernous nerve stimulation and the frequency and duration of spontaneous erections before and after cavernous nerve stimulation.


RESULTS
Sickle mice demonstrated significantly (P <.05) enhanced erectile responses to cavernous nerve stimulation and frequency of spontaneous erections both before and after cavernous nerve stimulation compared with the WT mice. The sickle mice penises had a significant decline in RhoA guanosine triphosphatase (P <.01) and total ROCK activities (P <.05) compared with the WT mice. A significant (P <.05) reduction in ROCK2 protein expression in sickle mice penises compared with WT mice protein expression. No change in ROCK1 protein expression was observed in either cohort of mice penises.


CONCLUSIONS
These data suggest that sickle cell disease associated-priapism might be contributed by a lack of RhoA/ROCK-mediated vasoconstriction and highlight a novel molecular mechanism in the pathophysiology of priapism.
Bivalacqua
Trinity J
TJ
James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. tbivala1@jhmi.edu
Ross
Ashley E
AE
Strong
Travis D
TD
Gebska
Milena A
MA
Musicki
Biljana
B
Champion
Hunter C
HC
Burnett
Arthur L
AL
D000755:Anemia, Sickle Cell / Q000150:complications / Q000201:enzymology; D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010413:Penis / Q000098:blood supply / Q000201:enzymology; D011317:Priapism / Q000201:enzymology* / Q000209:etiology*; D014661:Vasoconstriction; D054460:rho-Associated Kinases / Q000502:physiology*
D054460:rho-Associated Kinases