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Penile erection is a highly regulated physiological event that comprises of increased arterial inflow and restricted venous outflow, coordinated with smooth muscle cell (SMC) relaxation of the corpus cavernosum (CC), the vascularized smooth muscle of the penis. Erectile dysfunction (ED) affects 10% of adult males, rising to 60% at age 70. ED is now recognized to have pathophysiological causes in approximately 80% of cases, with diabetes and vascular disease major causes. Previous treatments for ED ranged from psychosexual counselling, drug treatments and surgically implanted prostheses providing penile rigidity. More recently, sildenafil (Viagra) has revolutionized the treatment of ED. Viagra inhibits phosphodiesterase-5, an enzyme that breaks down cGMP, an intracellular second messenger in the CC. cGMP is produced in response to nitric oxide (NO) production, the signaling molecule that relaxes the CC, allowing for blood engorgement and erection. Viagra and similar drugs are only effective in 70% of cases, decreasing to 50% in diabetics, many of which fail to respond to current drug therapies. Given the wealth of information regarding the role of the NO/cGMP pathway in penile erection, it is remarkable that our understanding of ED and the physiological processes that cause erection are inadequate. Indeed, the cells and molecular targets that produce cGMP in the CC have not been fully elucidated. The penile CC contains multiple cell types whose integrated responses lead to smooth muscle relaxation. Our preliminary experiments suggest a highly novel mechanism in which cGMP relaxes the CC. The CC, under unstimulated conditions, generates spontaneous transient depolarizations (STDs) and intracellular Ca2+-transients producing penile detumescence. Neural stimulation inhibits these events via NO/cGMP or enhances them via norepinephrine and acetylcholine release. STDs and Ca2+-oscillations depend on Ca2+ release from intracellular Ca2+ stores, not from SMCs but from a dense population of specialized PDGFRa+ interstitial cells within the CC, that form an electrical syncytium with neighboring SMCs regulating SMC excitability. This proposal, using state-of-the-art approaches, will provide groundbreaking discoveries that the cellular activities of PDGFRa+ cells are modulated by neuroeffector inputs that control CC excitability. The data will provide highly innovative breakthrough verification of a novel cellular target for the treatment of ED and enhance the rationale for future therapies.
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