Application of angiogenic factors for therapy of erectile dysfunction: protein and DNA transfer of VEGF 165 into the rat penis.

OBJECTIVES: To establish a laboratory animal model for vascular endothelial growth factor (VEGF) transfer in the rat penis to invent a curative therapy for erectile dysfunction (ED). Vascular insufficiency is a common pathomechanism of ED. Previous investigations have shown neovascularization of ischemic organs after gene transfer of VEGF. METHODS: For VEGF-protein transfer, osmotic pumps were connected to the renal arteries of rats. The pumps were filled with human VEGF 165 protein (n = 20) or sterile saline (n = 20). After 28 days, a VEGF serum immunoassay was performed to document successful delivery. For VEGF-DNA transfer, liposome complexes containing VEGF 165 expression vectors were injected into rat corpora cavernosa. After immunostaining, computerized image analysis was performed to quantify the percentage of area (within the corpora cavernosa) covered by smooth muscle or endothelial cells. RESULTS: The immunoassay of the VEGF-protein transfer showed a 10-fold greater VEGF concentration in the serum of rats carrying VEGF pumps than in the control group. In the VEGF-DNA transfer, the penes transfected with VEGF 165 vectors showed a 283-bp polymerase chain reaction product according to specific primers for human VEGF. Although statistical trends were measured in the VEGF protein-treated group, no statistically significant difference in smooth muscle or endothelial cell content was found between the control and VEGF-treated rats. CONCLUSIONS: Our findings have established proof of principle for successful delivery of VEGF protein and VEGF-DNA transfer in the rat penis. This study was a prelude to attempt to manipulate genetically expression of angiogenic factors in insufficient erectile tissue as a curative therapy for ED.

Inhibition of p53 function diminishes androgen receptor-mediated signaling in prostate cancer cell lines.

Current therapy for advanced prostate cancer is mainly based on androgen deprivation, although most patients relapse to androgen-insensitive disease. Several mechanisms contributing to androgen-independent growth including alterations in the structure or expression of the androgen receptor (AR) and its cofactors have been identified. Recent evidence suggests that p53 is involved in androgen signaling. The analysis of the effect of p53 on androgen signaling was performed in 22Rv1 and LNCaP prostate cancer cells that express both p53 and AR. The overexpression of p53 diminished the androgenic response in both cell lines in a reporter gene assay. Conversely, the inhibition of p53 by three different p53 inhibitors, Pifithrin-1alpha (PFT-1alpha), an inhibitor of p53-dependent transactivation; MDM2, a regulator of p53 expression; and a dominant-negative N-terminally truncated p53 gene also reduced transactivation of androgen-dependent reporter genes. The inactivation of p53 by PFT-1alpha decreased AR-protein expression in both 22Rv1 and LNCaP cells. Our findings confirm that the overexpression of wild-type p53 decreases androgen function, whereas p53 expression at physiological levels stabilizes AR signaling. Thus, our findings suggest that there is a balance of AR and p53 expression during the androgen-dependent growth of prostate cancer, which is obliterated during further progression of the disease.

Sexual dysfunction is common and overlooked in female patients with hypertension.

Our objective was to investigate sexual activity, behavior, dysfunction, and satisfaction in hypertensive women. Sixty-seven patients with a mean age of 60.4 years completed a detailed questionnaire. Of these women, 81.3% had a sex partner; 42.6% had untreated sexual dysfunction with a duration of more than 5 years in 70.9% and a duration of more than 10 years in 41.7%; 5.3% initiated sexual activity; 36.6% reported less sexual activity than desired; and 54.8% reported sexual activity as important. Our study revealed highly prevalent untreated sexual dysfunction of long duration. It also showed low frequency of sexual activity in spite of the high availability of partners. There was low frequency of initiation of sexual activity. In spite of the high prevalence of sexual dysfunction, more than a third of patients reported sexual activity to be less than desired, and more than half of patients reported sexual activity as important.