Nitric Oxide Synthesis Leads to Vascular Endothelial Growth Factor Synthesis via the NO/Cyclic Guanosine 3′,5′-Monophosphate (cGMP) Pathway in Human Corpus Cavernosal Smooth Muscle Cells

Authors


Akira Tsujimira, MD, PhD, Department of Urology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel: +81-6-6879-3531; Fax: +81-6-6879-3539; E-mail: akitsuji@uro.med.osaka-u.ac.jp

ABSTRACT

Introduction.  Vascular smooth muscle cells express endothelial nitric oxide synthase (eNOS) and produce nitric oxide (NO). Recently, increased NO production has been reported to induce the synthesis and secretion of vascular endothelial growth factor (VEGF) via the NO/cyclic guanosine 3′,5′-monophosphate (cGMP) pathway. L-arginine (L-arg), the precursor of NO, and selective phosphodiesterase type 5 (PDE-5) inhibitors that increase levels of intracellular cGMP may complementarily enhance VEGF synthesis in corpus cavernosal smooth muscle cells (CCSMCs), and may consequently restore impaired endothelial function. Expression of eNOS in corpus cavernosal smooth muscle has also been reported. However, it is unclear whether CCSMCs can generate NO.

Aim.  To elucidate whether CCSMCs can synthesize NO and whether NO synthesis enhances VEGF synthesis via the NO/cGMP pathway.

Methods.  Corpus cavernosal cells were cultured and characterized by immunocytochemistry and immunoblotting. CCSMCs were treated with L-arg. CCSMCs were also incubated with L-arg and with vardenafil, an inhibitor of PDE-5.

Main Outcome Measures.  Release of NO from cells was confirmed by assay of NO metabolites (NOx). Intracellular cGMP concentration and VEGF concentration in the medium were measured.

Results.  Isolated cells were determined to be CCSMCs. The expression of eNOS by CCSMCs was also identified. NOx and cGMP levels in the L-arg-treated group were significantly greater than those in the control group. VEGF and cGMP levels in the L-arg-treated group were also significantly greater than those in the control group. VEGF and cGMP levels in the L-arg + vardenafil-treated group were significantly greater than those in the L-arg-treated group and the control group.

Conclusions.  CCSMCs express eNOS and synthesize NO. NO synthesis leads to enhancement of VEGF synthesis via the NO/cGMP pathway. Combined L-arg and vardenafil treatment, which can enhance VEGF production, may provide a novel therapeutic strategy for the treatment of erectile dysfunction as well as endothelial dysfunction in general. Komori K, Tsujimura A, Takao T, Matsuoka Y, Miyagawa Y, Takada S, Nonomura N, and Okuyama A. nitric oxide synthesis leads to vascular endothelial growth factor synthesis via the no/cyclic guanosine 3′,5′-monophosphate (cGMP) pathway in human corpus cavernosal smooth muscle cells. J Sex Med 2008;5:1623–1635.

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