Reactive Oxygen Species Regulate Smooth Muscle Growth

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DESCRIPTION (provided by applicant): Uterine leiomyomas, or fibroids, are the most common pelvic tumors in women and are the primary indication for hysterectomy in the US. The incidence of symptomatic leiomyomas is 3-6 times higher in African American women than in other groups. While there may be a genetic component to this increased incidence we believe other factors may play a role. African-Americans show an increased incidence of hypertension, obesity and diabetes. Studies have shown that factors such as angiotensin II, serotonin and oleic acid, which are elevated in the bloodstream of patients with hypertension or obesity, have significant effects on proliferation and matrix production by vascular smooth muscle cells (SMCs) in response to injury. These factors, along with growth factors, regulate growth and differentiation of SMCs via a signaling pathway involving the production of reactive oxygen species (ROS). We hypothesize that similar ROS-dependent mechanisms are involved in the regulation of leiomyoma SMCs. The specific aims of this proposal are: 1. To determine whether ROS are a critical component of the EGF and PDGF signalling pathways in leiomyoma SMCs. 2. To determine whether angiotensin II, serotonin and oleic acid regulate proliferation and extra-cellular matrix production by leiomyoma SMCs and to determine whether these molecules act through their own receptors and/or by transactivating EGF or PDGF receptors. We will also determine the role of ROS in both of these activation pathways. 3. To determine whether halofuginone inhibits growth factor-stimulated proliferation and collagen production by leiomyoma SMCs by either inhibiting the increase in intracellular ROS or one of the downstream targets of ROS. The efficacy of halofuginone in an animal model of leiomyomas will also be assessed. The overall goal of this proposal is to elucidate the role of ROS in the signaling pathways that regulate growth and differentiation of leiomyoma SMCs. Molecules that inhibit ROS production or inhibit downstream targets of ROS may prove to be useful therapeutic agents for the treatment of leiomyomas. Halofuginorle has been shown to inhibit neointimal formation by vascular SMCs in rats undergoing angioplasty and tumor formation in nude mice. We believe halofuginone may act by inhibiting ROS-dependent signaling pathways in these cells as well as in leiomyoma SMCs.