MOLECULAR MECHANISMS OF CORPUS CAVERNOSUM FIBROSIS

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DESCRIPTION (Adapted from the Applicant's Abstract): Erectile dysfunction occurs in varying degrees in 18 - 30 million American men. Recent therapeutic advances, have been based on research that elucidated the physiologic mechanisms of erectile tissue (e.g. trabecular smooth muscle) relaxation. The trabecular smooth muscle cell, which is intimately involved in contractility, also synthesizes connective tissue. They have shown that a critical ratio of trabecular smooth muscle to erectile tissue collagen is required for normal erectile function. They have further shown that elevated corporal connective tissue content impairs overall erectile tissue "expendability" during tumescence, interfering with sub-tunical venule occlusion, resulting in venous leakage. Vasculogenic impotence secondary to veno-occlusive dysfunction from structural changes is a common cause of erectile impairment and a major pathophysiology resulting in pharmacologic treatment failures and need for penile prosthesis insertion. One of the least studied aspects of erectile physiology is the mechanism(s) by which trabecular smooth muscle regulates connective tissue synthesis and degradation. Transforming growth factor-beta (TGF) is a pleiotropic cytokine which induces connective tissue synthesis and has been implicated in soft tissue fibrosis. They have shown that human corpus cavernosum expresses TGF. They have developed a human corpus cavernosum smooth muscle cell culture model which maintains functional and structural elements of connective tissue proteins. TGF induces collagen synthesis in this model. This synthesis was suppressed by prostaglandin E1, forskolin, isoproterenol and sodium nitroprusside, agents which elevate cyclic nucleotide levels. They propose to test if collagen synthesis and degradation in this model is regulated by substances which alter cyclic nucleotide levels. Using this model, they will: (1) investigate TGF- induced collagen synthesis and degradation, (2) determine the effects of cyclic nucleotide elevating agents on TGF-induced collagen synthesis and (3) investigate the effects of TGF and cyclic nucleotide elevating agents on TGF and PGE synthesis and expression of their receptors. Previous research on trabecular smooth muscle contractility has led to innovative therapeutic approaches to treat erectile dysfunction. It is anticipated that corporal collagen research will lead to novel pharmacologic prophylactic therapies to restore and/or preserve a functional trabecular smooth muscle content and maintain erectile potency.