Atherosclerosis-induced chronic ischemia causes bladder fibrosis and non-compliance in the rabbit

Purpose: The overall goal was to det;ermine whether chronic ischemia and hy percholesterolemia interfere with bladder function and structure. The roles of atherosclerosis-induced chronic ischemia and hypercholesterolemia in bl adder fibrosis and non-compliance were studied in the rabbit. The relations hip between ischemia-induced changes in the expression of transforming grow th factor-pi (TGF-beta 1) and basic fibroblast growth factor (bFGF) and the severity of bladder fibrosis was also investigated. Materials and Methods: Male New Zealand White rabbits were divided into chr onic bladder ischemia (CBI, n = 11), hypercholesterolemia (Hch, n = 8) and control (n = 8) groups. The CBI: group underwent balloon endothelial injury of the iliac arteries and received a 0.5% cholesterol diet. The Hch group received a 0.5% cholesterol diet alone. The control group was placed on a r egular diet. After 16 weeks, iliac artery and bladder wall blood flow measu rements, cystometrograms (CMG) and aorto-iliac arteriograms were obtained i n all animals. Iliac arteries and bladder tissues were processed for histol ogical staining and computer-assisted histomorphometric image analysis, The expressions of TGF-beta 1 and bFGF in bladder tissue were determined by im munohistochemical staining utilizing monoclonal antibodies. Results: At 16 weeks, arteriography and histology showed significant diffus e atherosclerotic occlusive disease of the aorto-iliac arteries in the CBI group. Iliac;artery and bladder wall blood flows were significantly decreas ed in the CBI group compared with the Hch and control groups. Atheroscleros is-induced CBI shifted the volume-pressure curve to the left and caused sev ere bladder fibrosis. Hypercholesterolemia also caused fibrosis and non-com pliance but to a much lesser extent compared with those caused by CBI. In h istomorphometry, the percentage of detrusor smooth muscle was moderately de creased in the Hch group and severely decreased in the CBI group compared w ith the control group. In immunohistochemical stains of bladder tissues, bF GF expression was similar in the three groups of animals. TGF-beta 1 expres sion was significantly greater in bladder tissues from the CBI group compar ed with the Hch and control groups. Conclusions: Our studies show that atherosclerosis induced chronic ischemia increases TGF-beta 1 expression in the bladder leading to fibrosis, smooth muscle atrophy and non-compliance. Hypercholesterolemia also interferes wi th bladder structure and compliance but to a significantly lesser extent co mpared with CBI. Our studies suggest that arterial insufficiency and hyperc holesterolemia, common aging-associated disorders, may play important roles in the pathophysiology of voiding dysfunction in the elderly.