Interstitial cystitis/painful bladder syndrome (IC/PBS) is a debilitating disorder characterized by pain that is relieved by voiding, symptoms of pelvic pressure or discomfort, and an urgent need to urinate day and night. Many patients experience a worsening of their symptoms due to emotional or physical stress. Moreover, pain, frequency and urgency, and lack of sleep experienced by IC patients may themselves be a significant cause of stress. The diagnosis is primarily based on symptoms and there are no consistently effective treatments for IC. In the military, of the 1,737 patients in the deployed female active duty population in support of Operation Iraqi Freedom between 2003-2004, 150 patients were identified as having a pelvic pain disorder1. These patients accounted for 14% of all patients seen for gynecologic services. Mean age was 28 +/- 8 years (range, 15-53 years). In addition, pelvic pain of unclear etiology and cystitis were the most common diagnoses made accounting for 19% and 16% of encounters. The high incidences of pelvic pain in soldiers that are enduring the extremely stressful condition of the desert of Iraq indicate that this syndrome has a direct military implication. In addition, the harsh conditions of the desert alter drinking and voiding behaviors with unknown consequences to the physiology and pathophysiology of the lower urinary tract. Unfortunately, there is no information on the number of males in active duty that reported IC/PBS symptoms or the prevalence of this disorder in soldiers returning from active duty.

During bladder examination by endoscopy, patients with IC/PBS present glomerulations (pinpoint bleeding) in the bladder wall indicating that their blood vessels are fragile. Recently, the incidence of glomerulations in IC/PBS patients was highly associated with the elevated quantities of endothelial cell growth factor (VEGF). We found that patients with IC/PBS present fundamental alterations in VEGF not only in the blood vessels but also in cells lining the bladder surface (epithelium).

Our hypothesis is that, regardless of the cause of IC/PBS, bacteria infection or noxious substance in the urine that disrupts the epithelial barrier, the urinary bladder responds by increasing the production of VEGF that acts initially as a survival factor. However, VEGF also has the capacity for increasing vascular permeability leading to glomerulations, edema, and inflammation. Moreover, due to elevated numbers of VEGF receptors in the urothelium, the increased levels of VEGF further increase bladder permeability and establish a vicious cycle that perpetuates the disease. Therefore, blocking the VEGF signaling pathway should reduce the basic mechanisms involved in the genesis of IC/PBS. Because VEGF is an important factor in cancer prevention, several potent drugs have already been developed and are approved for use in humans. These potent drugs neutralize the effects of VEGF.

The likely contributions of this study in advancing the field of research include: At the end of year 1, we will have a better understanding of the basic mechanisms involved in VEGF-induced alteration of bladder blood vessels, edema, and inflammation. In year 2, we will define the efficacy of a VEGF neutralizing drug in blocking alterations in bladder blood vessels, edema, and inflammation. Finally, in year 3, we will test new and potent drugs that decrease the activity of VEGF receptors.

The innovative aspect of this proposal is to test a new application for these potent VEGF neutralizing agents using an established mouse model of inflammation, edema, and vascular bleeding. In addition, this project will introduce new modalities for imaging living organisms without perturbing them. The new contrast agents such as VEGF itself combined with a dye (Cy5.5) will permit us to image very fine changes in bladder blood vessels and opens up an incredible number of exciting possibilities for medical application, including early detection and treatment of IC/PBS, as well as basic pharmaceutical development. Furthermore, the imaging techniques here introduced allow for quantitative tests, adding a level of objectivity to the study of these areas.