Angiogenesis and Carpal Tunnel Syndrome

ABSTRACT

Although carpal tunnel syndrome is a fairly common condition, a limited understanding of its molecular pathogenesis exists. Clinicians remain perplexed as to the nature of the altered vascularity of the median nerve observed at surgical decompression. It is fairly well accepted that vascular endothelial growth factor is a potent mitogen for endothelial cells. Recent data has shown that Schwann cells themselves are the principle source of vascular endothelial growth factor in the peripheral nervous system and may direct angiogenesis. As such, we explored the possibility that Schwann cells and vascular endothelial growth factor played a role in the altered vascularity resulting from chronic nerve compression.

A previously described model of chronic nerve compression was used with Sprague-Dawley rats. Nonconstrictive silastic tubing (inner diameter 1.3 mm) was atraumatically placed around the right sciatic nerve of each animal. Nerve specimens were harvested at the 2 week, 1 month, 3 month, and 6 month time points after nerve conduction velocity/electromyogram (NCV/EMG) recordings. Nonisotopic in-situ hybridization and fluorescent immunohistochemistry were used to evaluate mRNA and protein expression of vascular endothelial growth factor and its receptors flk-1 and flt-1 at each time point. The number of blood vessels present in each nerve also was counted to determine the functional effect of vascular endothelial growth factor expression.

As previously reported, no statistically significant change was noted in NCV until 3 months. By 6 months, a 65% decrease in NCV was noted. Results from in-situ hybridization and immunohistochemistry demonstrated a marked increase in both mRNA and protein expression of vascular endothelial growth factor 165. The tyrosine kinase receptors for vascular endothelial growth factor flk-1 and flt-1 also demonstrated significant up-regulation in the chronic nerve compression nerve specimens. Functionally, a marked increase was noted in the number of blood vessels present at 6 months compared to earlier harvested specimens.

A distinct spatial and temporal pattern of up-regulation of vascular endothelial growth factor and its receptors with chronic nerve compression mirrors the dramatic increase in Schwann cell proliferation seen with chronic nerve compression. The data suggest the change in Schwann cell proliferation may be secondary to the up-regulation of vascular endothelial growth factor and its receptors. By better understanding the pathogenesis of chronic nerve compression, the treatment of carpal tunnel syndrome may be enhanced through targeted gene therapy.