Increased Cavernous Expression of Transforming Growth Factor-β1 and Activation of the Smad Signaling Pathway Affects Erectile Dysfunction in Men with Spinal Cord Injury

Abstract

Introduction Transforming growth factor-β1 (TGF-β1) is implicated in bladder fibrosis after spinal cord injury (SCI) and in the fibrosis in the corpus cavernosum tissue after cavernous nerve injury. Aim We investigated the differential expression of TGF-β1 and the Smad transcription factor, the key molecule for the initiation of TGF-β-mediated fibrosis, in cavernous tissue from SCI patients. Methods After obtaining informed consent and approval from the patients and our institutional review board, we enrolled 5 patients with psychogenic erectile dysfunction (ED) (mean age 36.8 years; range 20–50 years) and 10 patients with neurogenic ED from SCI (mean age 38.8 years; range 18–50 years). Cavernous tissues were obtained by percutaneous biopsy and stained with Masson trichrome, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL), or antibodies to TGF-β1 and phospho-Smad2. Main Outcome Measures Semi-quantitative analysis of TGF-β1 and phospho-Smad2 was performed, and the numbers of apoptotic cells were counted. We also quantified the cavernous collagen area with the use of an image analyzer system. Results The expression of TGF-β1 and phospho-Smad2 protein was significantly higher in the SCI group than in the psychogenic group. The TUNEL assay revealed a higher apoptotic index in the SCI group than in the psychogenic group. Higher TGF-β1 and phospho-Smad2 expression and more apoptotic cells were noted mainly in endothelial cells, smooth muscle cells, and fibroblasts of the SCI group. Double labeling of cavernous tissue with TUNEL and antibody to phospho-Smad2 revealed that most TUNEL-positive cells showed immunoreactivity to phospho-Smad2 staining. Cavernous collagen content was significantly greater in the SCI group than in the psychogenic group. Conclusion Upregulation of TGF-β1 and activation of the Smad signaling pathway may play important roles in SCI-induced cavernous fibrosis and deterioration of erectile function, which warrants early pharmacological intervention to protect erectile tissue from irreversible damage.

Calpain Inhibition Improves Erectile Function in a Rat Model of Cavernous Nerve Injury

“…It has been hypothesized that cavernosal nerve damage, such as that after radical prostatectomy, is associated with hypoxia-induced activation of the TGF-β1/Smad signaling pathway in the corpus cavernosum, which further leads to fibrosis and loss of smooth muscle content in erectile tissue [6,7] . Results from the current study confirmed previous reports showing activation of the TGF-β1/Smad2 pathway and increased collagen content in CN-crushed rats.…”

“…Following phosphorylated, Smad2 translocates to the nucleus and regulates the transcription of TGF-β target genes. It has been reported that upregulation of the TGF-β1/Smad signaling pathway might play an important role in ED-associated cavernosal fibrosis [7,9] . As a result of this denervation and structural changes in erectile tissue, often severe and difficult-to-treat ED develops.…”

The effect of long-term oral tadalafil treatment on corpus cavernosum function in an experimental spinal cord transection rat model

“…Acute SCI permits phasic penile erection, and these sexual reflexes can be observed during several weeks in the rat without significant changes. 16 Shin et al 17 reported that apoptosis, collagen deposition, smooth muscle cell loss and fibrosis were increased in the corpus cavernoum tissue specimens obtained by percutaneous biopsy from 10 SCIinduced ED patients. The authors also suggested that the patients might benefit from early pharmacotherapy (PDE-5 inhibitors) to prevent this irreversible injury.…”

Sexual and reproductive abnormalities in patients with spinal cord injuries

“…Sinirsel uyarımın kaybolduğu/azaldığı spinal kord ve periferik sinir lezyonlu erektil disfonksiyonlu olgularda süregen fibrozise yol açan kavernozal transforming growth faktör beta-1 (TGF-β1) yoğunluğu artmış bulunmuştur. [32] Spinal kord yaralanmalarında ejakulasyon işlevi de etkilenir. [12,33] Ejakulasyonun otonomik komponenti emisyon, somatik komponenti ekspulsiyondur (Şekil 2).…”

“…[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] Torakolomber bölge ile sakral merkezler arasındaki spinal kord lezyonlarında refleks ereksiyonlar görülürken psikojenik ereksiyon oluşmaz. [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] Ancak bu seviyede lezyonu olan olgularda psikojenik ereksiyonların da görülebildiği rapor edilmiştir. Bu durum torakolomber bölgenin altında paravertebral gongliyonlardaki parasempatiklerin normal kalması ve azalmış hipogastrik (sempatik) tonusa bağlı nöroplastite ile açıklanmıştır.…”