VCAM-1 expression on human dermal microvascular endothelial cells is directly and specifically up-regulated by substance P

Sensory nerves in skin are capable of releasing multiple neuropeptides, whi ch modulate inflammatory responses by activating specific cutaneous target cells. Extravasation of particular subsets of leukocytes depends upon the r egulated expression of cellular adhesion molecules such as VCAM-1 on microv ascular endothelial cells, We examined the direct effect of cutaneous neuro peptides on the expression and function of human dermal microvascular endot helial cell (HDMEC) VCAM-1. A significant increase in VCAM-1 immunostaining of microvascular endothelium was observed in vivo following capsaicin appl ication to human skin. Multiple cutaneous sensory C-fiber-released neuropep tides were evaluated for their ability to induce VCAM-1 cell surface expres sion on HDMEC. Only substance P (SP) was found to be capable of inducing HD MEC VCAM-1 expression, This SP-mediated VCAM-1 induction appeared to be a d irect effect that did not require the release of other HDMEC-derived solubl e factors, Increased HDMEC VCAM-1 mRNA expression was detected 1 h after th e addition of SP, with peak mRNA increase at 6-9 h postinduction. PACS stud ies demonstrated a 6.5-fold increase in endothelial cell surface VCAM-1 exp ression detectable 16 h after addition of SP, which was specifically blocke d by a neurokinin-l receptor antagonist, Increased VCAM-1 cell surface expr ession on SP-treated HDMEC resulted in a 4-fold increase in the functional binding of Cr-51-labeled MOLT-4 T cells. These data indicate that SP is cap able of directly and specifically up-regulating functional endothelial VCAM -1 expression and thus may play a key role in modulating certain inflammato ry responses in the skin.