Enhancement of Angiogenesis by Endogenous Substance P Release and Neurokinin-1 Receptors During Neurogenic Inflammation

Abstract

Early angiogenesis is a key step in the transition from acute to persistent inflammation. The nervous system has long been known to play a role in inflammation, in part through the release of substance P from peripheral nerve terminals (neurogenic inflammation). Application of substance P can stimulate vessel growth in a variety of angiogenesis assays, although it was previously not known whether endogenous substance P released from sensory nerves could modulate angiogenesis. We hypothesized that endogenous substance P can initiate angiogenesis during acute neurogenic inflammation. Here we show that 10 nmol of substance P can stimulate angiogenesis within the rat knee synovium, as shown by increased endothelial cell proliferation index [PCNA index, 19% (95% confidence interval (CI), 17 to 20%)] compared with saline injected knees [6% (95% CI, 4% to 8%), p Ͻ 0.05]. Moreover, this was prevented by coadministration of an antagonist of the neurokinin-1 (NK 1 ) subtype of neurokinin receptor SR140333 (nolpitantium), 1 mol [8% (95% CI, 5% to 11%)]. Capsaicin 0.5%, which stimulates release of endogenous substance P from sensory nerves, was also found to enhance synovial angiogenesis, [PCNA index 17% (95% CI, 14% to 19%)] compared with saline injected control knees [2% (95% CI, 1% to 3%), p Ͻ 0.05], and this also was inhibited by 1 mol of SR140333 [11% (95% CI, 8 to 16%)]. Inhibition of capsaicin-enhanced angiogenesis was incomplete, and this may indicate a contribution of other neuropeptides, in addition to substance P-NK 1 receptor interactions, in capsaicin-enhanced angiogenesis. NK 1 receptor antagonists could have therapeutic potential in conditions where neurogenic angiogenesis contributes to disease.

The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines

“…17,37 Furthermore, neoangiogenesis is a sequential process with early endothelial proliferation, followed by vessel neoformation and increased blood NK-1 receptor and aprepitant in melanomas M Muñ oz et al flow; the maturation of endogenous neurovascular regulatory systems occurs late in this process in inflamed tissues. 38,39 Vessel neoformation has also been associated with increased tissue innervation and expression of NK-1 receptors; 20 indeed, in a large majority of the tumors investigated, NK-1 receptors have been found on intratumoral and peritumoral blood vessels 19 and this finding is in agreement with the results reported herein. In addition, both SP and histamine (released from mast cells by the action of SP) are often concentrated in the connective tissue surrounding many tumors, including melanomas, and become so before the development of neoangiogenesis.…”

Capsaicin Inhibits in Vitro and in Vivo Angiogenesis

“…Notably, in contrast to antiangiogenic action of capsaicin in our system, capsaicin is reported recently to promote the neurogenic enhancement of angiogenesis in rat knee synovitis (43). Indeed, it was shown that intra-articular injection with high doses of capsaicin indirectly increases endothelial cell proliferation via release of endogenous substance P, an angiogenic neuropeptide, from sensory nerves.…”

Nonclassic Endogenous Novel Regulators of Angiogenesis

“…In vivo experiments showed that endogenous substance P could be implicated in the neoangiogenesis connected with neurogenic inflammation (Seegers et al, 2003). Substance P and capsaicin, which induces substance P release from sensory nerve terminals, were injected in the rat knee and animals were sacrificed 24 h later.…”