Effect of endothelial cell-based iNOS gene transfer on cavernosal eNOS expression and mouse erectile responses

Area of Science:

• Cardiovascular Biology
• Gene Therapy
• Urology

Background:

• Inducible nitric oxide synthase (iNOS) gene transfer has shown mixed results, enhancing erectile responses in rats but impairing cerebral artery vasorelaxation.
• Endothelial cells (EC) play a crucial role in regulating vascular function and erectile responses.

Purpose of the Study:

• To investigate the impact of endothelial cell-based iNOS gene transfer on endothelial NOS (eNOS) expression and erectile function in mice.
• To determine the mechanism underlying changes in eNOS expression following iNOS gene transfer.

Main Methods:

• Human coronary artery ECs were transduced with iNOS or an empty vector, then transplanted into the corpus cavernosum of immunodeficient mice.
• eNOS expression was analyzed in vitro with and without a selective iNOS inhibitor (L-NIL).
• In vivo, erectile responses (intracorporeal pressure) and cavernosal eNOS expression were measured after cell transplantation.

Main Results:

• iNOS-transduced ECs produced more nitric oxide (NO) but showed a twofold downregulation of eNOS protein and mRNA, an effect reversible by L-NIL.
• Mice receiving iNOS-transduced ECs exhibited significantly increased erectile responses (ICP) compared to controls.
• Cavernosal tissues from these mice displayed reduced eNOS expression, consistent with in vitro findings.

Conclusions:

• Endothelial cell gene transfer of iNOS downregulates eNOS expression via an NOS-dependent mechanism.
• Short-term iNOS gene transfer augmented erectile responses, but the concurrent downregulation of eNOS suggests potential adverse effects on endothelial function for long-term erectile dysfunction treatment.