SIV-induced impairment of neurovascular repair: a potential role for VEGF.

Peripheral nerves and blood vessels travel together closely during development but little is known about their interactions post-injury. The SIV-infected pigtailed macaque model of human immunodeficiency virus (HIV) recapitulates peripheral nervous system pathology of HIV infection. In this study, we assessed the effect of SIV infection on neurovascular regrowth using a validated excisional axotomy model. Six uninfected and five SIV-infected macaques were studied 14 and 70 days after axotomy to characterize regenerating vessels and axons. Blood vessel extension preceded the appearance of regenerating nerve fibers suggesting that vessels serve as scaffolding to guide regenerating axons through extracellular matrix. Vascular endothelial growth factor (VEGF) was expressed along vascular silhouettes by endothelial cells, pericytes, and perivascular cells. VEGF expression correlated with dermal nerve (r=0.68, p=0.01) and epidermal nerve fiber regrowth (r=0.63, p=0.02). No difference in blood vessel growth was observed between SIV-infected and control macaques. In contrast, SIV-infected animals demonstrated altered length, pruning and arborization of nerve fibers as well as alteration of VEGF expression. These results reinforce earlier human primate findings that vessel growth precedes and influences axonal regeneration. The consistency of these observations across human and non-human primates validates the use of the pigtailed-macaque as a preclinical model.