Diabetes, hypertension, hyperlipidemia and cigarette smoking all cause endothelial dysfunction. How penile endothelium contributes to cavernosal homeostasis and the pathophysiology of erectile dysfunction (ED) remains incompletely understood. Human cavernosal endothelium expresses a sinusoidal phenotype reflecting the unique range of physical forces and blood flow required for penile erection. These endothelial cells also contain complex regulatory and functional proteins such as eNOS and VEGF which participate in vasorelaxation, permeability regulation and vascular homeostasis. The objective of this proposal is to develop a tissue specific cellular tool to enhance our understanding of erectile physiology and the study of endothelium specific mechanisms of ED in vitro.
The Specific Aims of this proposal are to 1) Characterize the transcriptional profile of cavernosal endothelium in vitro and 2) Conditionally immortalize the human corpus cavernosal endothelial cell (hCCEC).
Aim 1 will use Affymetrix chips hybridized at the UW Center for Expression Arrays to characterize the gene programs and transcriptome of the in vitro human cavernosal endothelial cell isolated from normal donors.
Aim 2 will use unique retroviral vectors to conditionally immortalize hCCEC with either HPV E6/7 or hTERT. The goal will be to produce a cell line that express eNOS and VEGF receptors and respond to fluid shear stress. By achieving the goals of this proposal, we will provide a tool to facilitate the in vitro study of penile vascular function as well as mechanisms of ED due to metabolic conditions such as diabetes, hypercholesterolemia, and smoking. Furthermore, this cell system could be used to identify novel drugs targeting the penile endothelium and have applications in the area of tissue engineering and the investigation of endothelial-stromal interactions in the penis.
| Wessells, Hunter; Sullivan, Chris J; Tsubota, Yoshiaki et al. (2009) Transcriptional profiling of human cavernosal endothelial cells reveals distinctive cell adhesion phenotype and role for claudin 11 in vascular barrier function. Physiol Genomics 39:100-8 |
