Introduction: Although carpal tunnel syndrome is a fairly common condition, there remains a limited understanding of its molecular pathogenesis. Clinicians remain perplexed as to the nature of the altered vascularity of the median nerve observed at the time of surgical decompression. It is fairly well accepted that vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial cells. Recent data has shown that Schwann cells themselves are the principle source of VEGF in the peripheral nervous system and may actually direct angiogenesis (1). As such, we explored the possibility that Schwann cells and VEGF played a role in the altered vascularity resulting from chronic nerve compression (CNC).

Materials & Methods: A previously described model of CNC was used with Sprague-Dawley rats (2). Non-constrictive silastic tubing (I.D. 1.3mm) 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 EMG/NCV recordings. Non-isotopic in-situ hybridization (probes from Dr. J.A. Helms, UCSF) and fluorescent immunohistochemistry (IHC) 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 was also counted to determine the functional effect of VEGF expression.

Results: As previously reported, there was no statistically significant change in NCV until the 3 month time point. By the six month time point, there was a 65% decrease in NCV. Results from in-situ hybridization and IHC demonstrated a marked increase in both mRNA and protein expression of VEGF165. The tyrosine kinase receptors for VEGF, flk-1 and flt-1, also demonstrated significant up-regulation in the CNC nerve specimens. Functionally, there was a marked increase in the number of blood vessels present at the six month time point, as compared to earlier harvested specimens.

Discussion: There is a distinct spatial and temporal pattern of up-regulation of VEGF and its receptors with CNC that mirrors the dramatic increase in Schwann cell proliferation seen with CNC (2). The data suggests that the change in Schwann cell proliferation may be secondary to the up-regulation of VEGF and its receptors. By better understanding the pathogenesis of CNC, we may be able to enhance the treatment of carpal tunnel syndrome through targeted gene therapy. (1) Mukouyama et al. Cell 109: 693-705, 2002. (2) Gupta R and Steward. J Comp Neuro 461:174-186, 2003.