Hypoxia and an Angiogenic Response in the Partially Obstructed Rat Bladder

Abstract

SUMMARY: Previous molecular and blood flow studies performed on animal models of partial bladder outlet obstruction (PBOO) caused us to propose that bladder hypoxia/ischemia was a significant effector of the cellular and functional changes that occur in the bladder as a result of this condition. To confirm the occurrence of hypoxia in the partially obstructed bladder, we obtained rat bladders at increasing intervals following PBOO and measured biomarkers of hypoxia (intracellular formation of hypoxyprobe-1 adducts and expression of hypoxia inducible factor-1␣ [HIF-1␣] protein) and whether such hypoxia might elicit an angiogenic response in the tissue. Rats receiving PBOO or controls were treated with hypoxyprobe-1 at increasing intervals subsequent to surgery and their bladders were sectioned and immunostained using an antibody that detects hypoxyprobe-1 adducts. Control rat bladders were unstained, whereas intense, but regionally restricted, hypoxyprobe-1 immunostaining was detected in all obstructed bladders in a unique pattern that changed over time. Proteins were extracted from bladders removed from similarly treated rats and were analyzed for the expression of the HIF-1␣ protein as well as for expression of angiogenic regulatory factors (vascular endothelial growth factor, angiopoietin-1, and endostatin) using Western blotting techniques. HIF-1␣ protein was not expressed in control bladders, however, the protein was highly up-regulated over the 2-week period after PBOO. Likewise, the expression of vascular endothelial growth factor (a downstream target of HIF-1␣ action) and angiopoietin-1 was also up-regulated in obstructed bladders confirming an angiogenic response to this hypoxia. Enigmatically, however, expression of the antiangiogenic molecule endostatin was also up-regulated by chronic PBOO. These results further support the concept that hypoxia is involved in the cellular remodeling as well as in the progressive functional impairment exhibited by the urinary bladder after PBOO. (Lab Invest 2002, 82:903-909).

Angiogenic Switch of Angiopietins-Tie2 System and Its Prognostic Value in Bladder Cancer

“…In presence of vascular endothelial growth factor (VEGF), Ang-2 potentiates angiogenesis, whereas, in the absence of VEGF, the vessels may regress (2,6). Hypoxia initiates a change in Ang-1/Ang-2 ratio in favor of Ang-2 and results in vessel destabilization (7). VEGF is also induced by hypoxia and can drive the destabilized vessels toward angiogenesis.…”

Tacrolimus (FK506) Limits Accumulation of Granulocytes and Platelets and Protects against Brain Damage after Transient Focal Cerebral Ischemia in Rat

“…17) Using this method, we have previously reported that a hypoxic condition exists within cerebral cortex in rats at 3, 9 and 24 h after MCA occlusion for 60 min, and proposed that plugging of microvasculature with granulocytes and platelets would be responsible for the hypoxic condition. 18) We also reported that tacrolimus attenuated cortical neuronal damage slightly at 9 h, with a significant effect at 24 h after MCA occlusion.…”

Inhibition of vascular smooth muscle inward-rectifier K+channels restores myogenic tone in mouse urinary bladder arterioles

“…Prolonged hypoxia, caused by inflammation, outlet obstruction, or vesical artery occlusion, is correlated with prolonged decreases in bladder blood flow, progressive bladder dysfunction, and, ultimately, bladder necrosis if blood flow is not restored (2-4, 37, 49). Vesical artery occlusion and decreased blood flow are also associated with significant bladder wall remodeling processes, including collagen deposition, urothelial barrier disruption, and production of proangiogenic factors and reactive oxygen species (2,12,31). Collectively, these observations suggest that the bladder is extremely sensitive to changes in blood flow, as even a modest reduction in blood flow leads to hypoxia, and prolonged changes in blood flow can cause bladder overactivity and remodeling.…”