The effects of the vasoactive perivascular neuropeptides calcitonin gene-related peptide (CGRP), neurokinin A (NKA), neuropeptide Y (NPY), and vasoactive intestinal polypeptide (VIP) on proliferation of cultured human umbilical vein endothelial cells (HUVECs) were investigated. CGRP was shown to increase both cell number and DNA synthesis, whereas NKA, NPY, and VIP were ineffective. l I-labeled CGRP was shown to bind to HUVECs and this binding was displaced by addition of unlabeled CGRP, suggesting the existence of specific CGRP receptors. The effect of CGRP on formation of adenosine 3',5'-cycdic monophosphate (cAMP) and inositol phosphates (InsP), two intracellular messengers known to be involved in regulation of cell proliferation, was investigated. CGRP stimulated cAMP formation but was without effect on the formation of InsP. Proliferation, as well as cAMP formation, was also stimulated by cholera toxin. Basic fibroblast growth factor stimulated growth without affecting cAMP or InsP formation, whereas thrombin, which increased InsP formation, did not stimulate proliferation. We thus suggest that CGRP may act as a local factor stimulating proliferation of endothelial cells; that the mechanism of action is associated with cAMP formation; and that this effect of CGRP may be important for formation of new vessels during physiological and pathophysiological events such as ischemia, inflammation, and wound healing. Several different factors have been shown to stimulate the formation of new vessels, angiogenesis, and/or to be mitogenic for cultured endothelial cells. These factors include polypeptide growth factors-i.e., basic and acidic fibroblast growth factor (bFGF, aFGF)-endothelial cell growth factor, which is a precursor form of aFGF, transforming growth factors a and /3, angiogenin, and tumor necrosis factor a (1).Angiogenic factors may be important when released locally by cells adjacent to the endothelium, possibly also produced by the endothelial cells themselves or as circulating factors in plasma.Indirect evidence has suggested trophic effects of peripheral neurons. In the newt, naturally occurring limb regeneration is prevented by damage to the peripheral nerve innervating the limb (2). Intact sensory innervation has been shown to be important for corneal wound healing in the rat (3), and in humans suffering from Parry-Romberg syndrome, a marked hemifacial dystrophia is observed in the area innervated by the trigeminal nerve (4). Although direct evidence from in vivo studies is essentially lacking, recent studies have shown that sensory neuropeptides regulate cell proliferation in vitro. Neurokinin A (NKA) and substance P (SP), which are structurally related, have been shown to induce proliferation of human fibroblasts and rat smooth muscle cells (5). This effect was shown to be parallel with increased phosphatidylinositol (PI) turnover (6). Furthermore, vasoactive intestinal polypeptide (VIP) has been shown to inhibit serum-induced proliferation of rat smooth muscle cells and to stimulate prol...

Substance P (SP) has recently been reported to induce interleukin 1 (IL-1) production by human monocytes. This was confirmed in our experiments with human monocytes cultivated in the presence of SP or SP together with lipopolysaccharide (LPS). In addition, a wide variability of cell response to the neuropeptide was noticed. Three out of twelve cell cultures were directly stimulated by SP to release IL-1, while four additional cultures needed prestimulation with suboptimal doses of LPS, and no effect was seen in the five remaining experiments. The data may suggest that preferentially activated monocytes respond to SP. The production of IL-1 by SP-stimulated monocytes is of great interest considering the broad spectrum of activity of IL-1 and the increasing evidence of sensory neuron involvement in acute and chronic inflammatory responses.

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