Sildenafil became a blockbuster treatment of erectile dysfunction almost overnight, with sales reportedly totaling $1.5 billion in 2001. Despite its success and the improvements that are expected with the development of second-generation PDE5 inhibitors, this approach remains unsuitable for 30-50% of patients due to the severity of disease or to contra-indications. A sizable market therefore remains for the treatment of erectile dysfunction.

The major types of vascular problems that can result in erectile dysfunction are arterial insufficiency, inadequate impedance of venous outflow (venous leaks), or a combination of both. With age and underlying diseases especially atherosclerosis the amount of blood entering the penis is decreased impeding penile erection. As erectile dysfunction becomes more long-term, treatment becomes more difficult, partly due to an additional component of the disease coming into play, namely ischemia. Prolonged ischemia results in a loss of penile muscle mass and an increase in fibrosis. In this patient group optimal therapeutic strategies should include the use of molecules able to regenerate vascular smooth muscle rather than (or as well as) controlling the level of contractility of the existing musculature. Hence, the development of pro-angiogenic therapies for the treatment of erectile dysfunction may be beneficial to patients with severe disease. Animal studies have identified insulin-like growth factor (IGF-I) and vascular endothelial growth factor (VEGF) as penile angiogenic growth factors, but the role of these factors in humans is not well understood. American researchers have therefore evaluated the ex vivo expression of IGF-I, VEGF, and their receptors (IGF-IR, Flt-1, and KDR) in human penile cavernosal smooth muscle cells to identify cellular and molecular pathways involved in the regulation of penile tissue vascularity. IGF-I and VEGF and their receptors were identified in primary smooth muscle cultures. RT-PCR evaluation revealed the expression of four splice variants of VEGF messenger RNA (VEGFs 121, 145, 165, and 189) and two of its receptors (Flt-1 and KDR). VEGF165 and VEGF121 were the most abundant forms of messenger RNA and Flt-1 appeared to be the most prominent receptor type in these cells. Exposure to VEGF elicited a twofold to threefold increase in smooth muscle cell proliferation. These data add further support to the concept of targeting angiogenesis for the treatment of erectile dysfunction, an approach that has also been validated in a number of studies investigating the effects of VEGF on penile erection, and furthermore describe in greater details the molecular targets for such an approach.

Entry date January, 2003

Adapted from Rajasekaran et al, J Androl 2003 Jan-Feb;24(1):85-90 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.