Characterization of ureteral dysfunction in an experimental model of congenital bladder outlet obstruction

Purpose: Ureteral dysfunction is a significant sequela of congenital bladde r outlet obstruction. However, the structural and functional alterations as sociated with ureteral dysfunction are not well defined. A model of fetal b ladder obstruction in sheep was used to characterize the changes in uretera l smooth muscle, extracellular matrix (ECM) and functional properties in re sponse to bladder outlet obstruction. Materials and Methods: Partial bladder outlet obstruction was created in fe tal sheep at gestational age 95 days via placement of a metal ring around t he proximal urethra as well as ligation of the urachus. Ureters were harves ted at 109 and 135 days (full term = 140 days) to determine the relative co mposition of smooth muscle, ECM and urothelium by morphometric analysis and to measure DNA and protein concentrations. Ureteral tissue from 135 day ge station obstructed and control sheep was harvested and immediately placed i n Krebs solution. Smooth muscle strips (2-3 mm. x 7-8 mm.) were suspended i n organ baths. The frequency and amplitude of spontaneous ureteral contract ions was as well as the response to electric field stimulation (EFS) were d etermined, Results: Bladder outlet obstruction caused a significant increase in ureter al weight, smooth muscle mass and total ECM at both 109 and 135 days gestat ion. Total ureteral DNA was greater in obstructed compared with sham ureter s at 135 days gestation. Obstructed ureters demonstrated greater amplitude and frequency of spontaneous contractions as well as more pronounced respon se to EFS when compared to sham ureters. Conclusions: The fetal ureter responds to bladder obstruction with smooth m uscle hyperplasia and hypertrophy which is associated with increased sponta neous activity and augmented response to EFS. ECM content is markedly incre ased indicating a shift in the balance of connective tissue synthesis and d egradation. Congenital post-obstructive ureteral dysfunction therefore appe ars to be the result of dysregulated smooth muscle cell growth and altered ECM homeostasis producing abnormal ureteral contractility.