title: 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 < 0.05]. Moreover, this was prevented by coadministration of an antagonist of the neurokinin-1 (NK1) subtype of neurokinin receptor SR140333 (nolpitantium), 1 micro 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 < 0.05], and this also was inhibited by 1 micro 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-NK1 receptor interactions, in capsaicin-enhanced angiogenesis. NK1 receptor antagonists could have therapeutic potential in conditions where neurogenic angiogenesis contributes to disease.
authors.affiliation: Academic Rheumatology, University of Nottingham Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK.
authors.forename: Hélène C
authors.initials: HC
authors.lastname: Seegers
authors.forename: Vivienne C
authors.initials: VC
authors.lastname: Hood
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Kidd
authors.forename: Simon C
authors.initials: SC
authors.lastname: Cruwys
authors.forename: David A
authors.initials: DA
authors.lastname: Walsh
mesh_terms: D000818:Animals; D004727:Endothelium / Q000502:physiology; D007719:Knee Joint; D008264:Macrophages / Q000502:physiology; D008297:Male; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D020078:Neurogenic Inflammation / Q000503:physiopathology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D013373:Substance P / Q000502:physiology*
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D018040:Receptors, Neurokinin-1; D013373:Substance P