The pathogenetic basis for diabetic neuropathy has been enigmatic. Using tw
o different animal models of diabetes, we have investigated the hypothesis
that experimental diabetic neuropathy results from destruction of the vasa
nervorum and can be reversed by administration of an angiogenic growth fact
or. Nerve blood flow, as measured by laser Doppler imaging or direct detect
ion of a locally administered fluorescent lectin analogue, was markedly att
enuated in rats with streptozotocin-induced diabetes, consistent with a pro
found reduction in the number of vessels observed. A severe peripheral neur
opathy developed in parallel, characterized by significant slowing of motor
and sensory nerve conduction velocities, compared with nondiabetic control
animals. In contrast, 4 weeks after intramuscular gene transfer of plasmid
DNA encoding VEGF-1 or VEGF-2, vascularity and blood flow in the nerves of
treated animals were similar to those of nondiabetic control rats; constit
utive overexpression of both transgenes resulted in restoration of large an
d small fiber peripheral nerve function. Similar experiments performed in a
rabbit model of alloxan-induced diabetes produced comparable results. Thes
e findings support the notion that diabetic neuropathy results from microva
scular ischemia involving the vasa nervorum and suggest the feasibility of
a novel treatment strategy for patients in whom peripheral neuropathy const
itutes a secondary complication of diabetes.