Abstract
Neuropeptides are one of the most conserved proteins across different species and are ubiquitously expressed in different organs. In the peripheral nervous system, neuropeptides are secreted by the sensory and autonomic nerves and participate in a wide range of functions including immune surveillance, cardiovascular homeostasis, regulation of endocrine function, cytokine and growth factor release, and importantly angiogenesis. Neuropeptides including neuropeptide Y, substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and somatostatin (SS) are some of the neuropeptides that have been investigated regarding their role in modulating the vascular system and angiogenesis. All of these neuropeptides are pro-angiogenic except SS, which has anti-angiogenic properties. This chapter aims to present up-to-date evidence on the various mechanisms of action of the aforementioned neuropeptides and their clinical implications.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
1 Introduction
Neuropeptides are some of the most conserved and abundant peptides in vertebrates and function as neurotransmitters or neuromodulators or both within the central nervous system (CNS) and peripheral nervous system (PNS). Neuropeptides released from the PNS participate in major physiological functions ranging from cardiovascular homeostasis and gastrointestinal motility to immune cell trafficking. Neuropeptides including neuropeptide Y (NPY), substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and somatostatin (SS) have emerged as important regulators that affect the vascular system by modulating the vascular tone, angiogenesis, and vascular remodeling [1–10]. Most of these neuropeptides are pro-angiogenic, with the exception of SS, which has anti-angiogenic properties. Numerous studies have investigated the role of neuropeptides in angiogenesis, but there has been limited success in the development of neuropeptide-based therapies targeting angiogenesis. While some of the neuropeptides or neuropeptide-based therapeutics is in the pipeline for treatment of other diseases, so far, SS analogues are the only neuropeptide-based therapies used for modulating/inhibiting angiogenesis in cancer. This suggests that the ubiquitous and complicated neuropeptide signaling system in the vasculature needs a more in-depth understanding. Additionally, delivery of these peptides and their receptor agonists/antagonists to the target organ also poses various challenges.
This chapter aims to provide the most up-to-date information on the widely studied angiogenic neuropeptides, NPY, SP, CGRP, VIP, and SS. The reader has to note that this is not an exhaustive review but rather a concise summary that includes those neuropeptides that have received the most attention for their role in modulating angiogenesis.
2 Neuropeptide Y
NPY is a 36-amino acid peptide and is one of the most abundantly and ubiquitously distributed neurotransmitters in the CNS and PNS [11]. In the CNS, it is mainly expressed in the hypothalamus, [12] and in the PNS, it is found in sympathetic nerves, where it is stored either alone in small vesicles or in combination with catecholamines in larger vesicles [13, 14]. Moreover, NPY is also produced by vascular smooth muscle cells, endothelial cells (ECs), vas deferens cells, and pancreatic acinar cells [12, 15].
NPY signals through six subtypes of G protein-coupled receptors (GPCRs) including NPY1R, NPY2R, NPY3R, NPY4R, NPY5R, and NPY6R [16]. NPY regulates vascular tone by inducing vasoconstriction [17], stimulates vascular smooth muscle cell growth and hypertrophy of ventricular cardiomyocytes [18, 19], and is also involved in immune cross talk [20]. Signaling through NPY1R, NPY2R, and NPY5R is implicated in diabetes, heart failure, hypertension, peripheral arterial disease, and feeding disorders [21]. Furthermore, these receptors are involved in angiogenesis [22], calcium homeostasis [21], renin-angiotensin-aldosterone system (RAAS), and protein kinase C (PKC) activation of diabetes and heart failure [23].
3 NPY and Angiogenesis
In recent years, the contribution of NPY-associated angiogenesis to cardiovascular disease, wound healing, and cancer has received a lot of attention [1, 2, 24–26]. The first report that described the sympathetic co-transmitter NPY, as a pro-angiogenic molecule, was presented by Zukowska et al. and was based on work in human umbilical vein endothelial cells (HUVECs). The authors reported that not only the receptors NPY1R and NPY2R but also NPY itself and the enzyme, dipeptidyl peptidase (DPPIV) that converts NPY36 to the angiogenic NPY3–36, are expressed in these cells. Of the NPY receptors, NPY1R, NPY2R, and NPY5R are involved in angiogenesis. So far the only known mechanisms by which NPY leads to angiogenesis are release of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and NO [26, 27].
NPY1R antagonism is shown to inhibit angioplasty-induced atherosclerotic-like vascular remodeling, without affecting ischemic revascularization; NPY2R activation is shown to stimulate ischemic angiogenesis. NPY5R enhances the effect of both NPY1R and NPY2R [6, 25]. NPY1R is normally implicated in pathologies of the cardiovascular system including cardiac hypertrophy and vasoconstriction, whereas NPY2R and NPY5R are known to ameliorate ischemia and impaired wound healing. In a recent swine study of chronic myocardial ischemia, treatment with exogenous NPY3–36 increased capillary and arteriole formation along with upregulation of NPY1R, NPY2R, NPY5R, VEGF, endothelial nitric oxide synthase (eNOS), phospho-eNOS (p-eNOS) on Ser1177, and PDGF and a downregulation of anti-angiogenic factors endostatin and angiostatin in the NPY-treated group [26]. This suggests that NPY signaling occurs in a feed-forward pro-angiogenic manner where it enhances the entire NPY signaling system by upregulating its own receptors.
NPY has been demonstrated to have a role in the angiogenesis phase of wound healing in both cutaneous and tendon healing by acting through NPY2R and NPY5R [1, 28, 29]. In fact, in NPY2R knockout mice, angiogenesis and thereby wound healing are disrupted [8].
In cancer, NPY and its receptors are expressed in both the tumor cells and the tumor vasculature. In human neuroblastoma tissues, NPY is predominant in the tumor cells whereas NPY2R is expressed in both tumor and ECs, making NPY2R a promising target for neuroblastoma therapy [30]. Similarly, prostate tumors and neural crest-derived tumors release NPY that can facilitate tumor vascularization [31, 32]. These studies demonstrate an important role for NPY in the treatment of wound healing, ischemic revascularization, and cancer.
4 Substance P
SP is an 11-amino acid neurotransmitter and neuromodulator widely distributed in the CNS and PNS [13, 33]. SP is released from C-fiber sensory nerves, in primary sensory neurons and neurons intrinsic to the gastrointestinal, respiratory, and genitourinary tracts [34, 35]. SP binds to three G protein-coupled receptors, NK1R, NK2R, and NK3R, out of which NK1R is its high-affinity receptor that is present on a variety of cell types including immune cells, keratinocytes, ECs, neurons, and glial cells [36]. SP is involved in several physiological processes, including maintenance of cardiovascular tone, smooth muscle activity, vomiting reflex, defensive behavior, and stimulation of salivary secretion [9, 37]. SP has been shown to be mitogenic towards smooth muscle cells, fibroblasts, and ECs [1, 35, 38–40]. SP has shown to affect different pathways in different cell types including activation of phospholipase C producing a net rise in intracellular (Ca2+) and cAMP via AC [41, 42]; induction of cytokines, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8, IL-1β, and IL-2, from T lymphocytes, macrophages, and neutrophils [43]; activation of protein kinase B (Akt) pathway in dopaminergic neurons [44]; and induction of transforming growth factor-beta (TGF-β) from fibroblasts [45, 46].
5 SP and Angiogenesis
The vasodilatory effect of SP was evident long before nitric oxide (NO) was recognized as the endothelium-derived relaxation factor (EDRF) [47]. Only later, it was demonstrated that SP-induced vasodilation was indeed mediated by NO via the NK1R [48, 49]. The first evidence indicating the role of SP in EC proliferation and neovascularization was demonstrated by Ziche and colleagues in vitro in HUVECs and in vivo in an avascular cornea rabbit model [40]. Similar to NPY, SP-mediated angiogenesis via NK1R contributes to wound healing, tumor angiogenesis, and ischemic angiogenesis [1, 50–53]. SP plays a major role in cutaneous wound healing by participating in the inflammatory and angiogenic phases [35]. In vitro studies indicate that SP treatment leads to proliferation and tube formation of dermal microvascular ECs in normal and hyperglycemic conditions [1, 54, 55]. Moreover, inhibition of the enzyme neprilysin that breaks down SP also enhances angiogenesis [56]. In cutaneous wound healing, NO release is the only known mechanism through which SP has been shown to lead to angiogenesis. In addition to cutaneous wound healing, SP has also shown to aid in tendon healing after injury by augmenting angiogenesis [51, 57].
SP and NK1R are implicated in different cancers including brain tumors, melanomas, and breast cancer [58–60]. NK1R receptors are upregulated in brain tumors, and therefore NK1R antagonists that cause tumor cell apoptosis and also inhibit tumor vascularization hold great promise in treating these tumors [58, 61]. Aprepitant, the NK1R antagonist approved for the treatment of chemotherapy-induced nausea and vomiting, has shown some promising results in inhibiting cell growth of different melanoma cell lines [62]. However, at this time aprepitant has not been approved for any cancer treatment. The genes that encode SP, preprotachykinin 1, and NK1R and NK2R have shown to be upregulated in breast cancer, and NK1R antagonists have shown to inhibit breast cancer cell growth in in vivo models [60, 63]. Currently there are no studies targeting breast tumor angiogenesis with NK1R antagonists.
In a recent mouse hind limb ischemia study, SP has shown to mobilize NK1R-expressing progenitor cells from bone marrow and promote reparative angiogenesis [50]. In the same study, authors showed that patients with acute myocardial infarction had high circulating levels of SP and NK1R-positive cells that co-express progenitor cell antigens, which are abundant in infarcted hearts, but interestingly not in hearts that developed an infarct after transplantation [50].
These studies demonstrate that in addition to its role as a sensory neuropeptide, SP and its receptors also play an important role in wound healing, ischemic revascularization, and cancer.
6 Calcitonin Gene-Related Peptide
CGRP is a 37-amino acid peptide generated in the CNS and PNS from the alternate splicing of calcitonin gene mRNA in a tissue-specific manner [64]. In the PNS, CGRP is expressed in the nerves innervating the skin, gut, pancreas, heart, and the vasculature. It is co-localized with SP in the sensory nervous system and, similar to SP, is a potent vasodilator [65].
CGRP receptor is a heterodimer of calcitonin receptor-like receptor (CRLR), a GPCR, which is linked to receptor activity modifying protein (RAMP)1, RAMP2, or RAMP3 [66]. CRLR-RAMP1 is specific for CGRP while CRLR-RAMP2 and RAMP3 can also bind adrenomedullin, a related peptide [66]. CGRP is known to be involved in vasodilation, nociception, glucose uptake, and the stimulation of glycolysis in skeletal muscles [67]. Binding of CGRP to its receptors leads to an increase of cAMP and activation of protein kinase A (PKA), phospholipase C beta (PLCβ1), mitogen-activated protein kinase (MAPK), and production of NO [68].
7 CGRP and Angiogenesis
Similar to SP, CGRP was found to be a potent vasodilator that acted through an endothelial-dependent mechanism which later was identified to be NO [69, 70]. The first connection between CGRP and angiogenesis was identified in a rat ischemic skin flap partial denervation study where angiogenesis preceded reinnervation with CGRP positive nerves [71]. In a subsequent study, the same group showed that in fact CGRP at least partially contributed towards angiogenesis [72]. Similar to SP, CGRP-associated angiogenesis is involved in wound healing, ischemic revascularization and tumor vascularization. In a rat knee-joint model intra-articular CGRP injection increased endothelial cell proliferation while inhibition of CRLR-RAMP1 attenuated EC proliferation in capsaicin-induced knee-joint synovitis [73]. In a model of rat hind limb ischemia, CGRP levels were elevated in the ischemic tissue, and over-expression of CGRP enhanced blood flow recovery and increased capillary density in ischemic hind limbs most likely via activation of AMP-activated protein kinase (AMPK) [74]. In vitro, CGRP induced p-eNOS in HUVECs at Ser1177 and Ser633 in a time-dependent manner, and these effects were abolished by AMPK inhibition [74]. In addition to AMPK and eNOS, CGRP has also shown to enhance angiogenesis in cutaneous and gastric mucosal healing via VEGF [75, 76]. In CGRP knockout mice, tumor growth and tumor-associated angiogenesis of implanted Lewis lung carcinoma (LLC) cells along with downregulation of VEGF expression in tumor stroma were significantly reduced compared with those in wild-type mice [77].
CGRP is very similar to SP in its angiogenic profile and can serve as an important target for wound healing and cancer.
8 Vasoactive Intestinal Peptide
VIP is a 28-amino acid peptide that is expressed all throughout the CNS including the hypothalamus, PNS, intestines, pancreas, urogenital tract, thyroid, and adrenal glands [78].
VIP affects a wide range of biological activities including vasodilation and smooth muscle relaxation, stimulation of pepsinogen secretion by the chief cells of the gut, secretion of water and electrolytes into the intestines, enhancement of glycogen metabolism in the cerebral cortex, regulation of embryonic growth, promotion of neuronal survival, and modulation of the immune system as well as mammalian circadian rhythm [78]. VIP exerts its biological effects through its receptors, vasoactive intestinal polypeptide receptor 1 (VPAC1) and VPAC2 which are GPCRs. Receptor activation leads to modulating the activity of phospholipase D (PLD) and also increased cAMP and intracellular calcium levels [78].
9 VIP and Angiogenesis
Similar to SP and CGRP, VIP was identified as a vasodilator in a canine model where VIP was injected in the glandular artery of the submandibular gland [79]. Later it was demonstrated that VIP-induced vasodilation is also mediated via l-arginine-NO pathway [80]. VIP-associated angiogenesis is implicated in tumor vascularization with some studies demonstrating its protective role in ischemic injury. Although VIP is shown to aid in wound healing, most of this effect is attributed to its role in bronchial epithelial cell proliferation [81] and keratinocyte proliferation [82, 83] but not through angiogenesis. In addition to increasing EC proliferation, VIP is also known to increase EC migration [84]. In a model of acute cerebral ischemia, a single dose of intracerebroventricular injection of VIP at the beginning of reperfusion led to increased number of ECs and microvessels at the boundary of the ischemic lesion. VIP further significantly increased VEGF levels in the ischemic hemisphere as well as VEGF receptor flt-1 and flk-1 immunoreactivity in Ecs [85, 86].
In the human small lung cancer cell line H446 VIP administration increased c-fos and VEGF mRNA expression that was reversed by c-fos antisense oligodeoxynucleotide [87]. In a mouse xenograft model in which human prostate cancer cells were transplanted, VIP administration resulted in increased tumor growth along with increased VEGF expression [88]. In another study, the same group showed that VIP induces VEGF mRNA expression via c-fos, which in turn is induced by calcium signaling in human prostate LNCaP cells [89]. In a colon carcinoma model, systemic VIP treatment reduced angiogenesis within tumor masses by cAMP-dependent mechanism [90].
Similar to NPY, SP, and CGRP, VIP has been shown to play a role in ischemic vascularization and in cancer angiogenesis; however, its role in the angiogenic phase of wound healing has not yet been investigated. Given the angiogenic profile of VIP, it would not be too far-fetched to surmise that VIP could promote wound healing.
10 Somatostatin
Somatostatin (SS) which was discovered in 1974 by Brazeau et al. [91] is a major inhibitory neuropeptide produced in the hypothalamus and the arcuate nucleus but also secreted by peripheral nerves in the gut [92, 93]. In fact, the gastrointestinal tract contains about 70 % of the total SS [94]. SS exists in three forms, the 14 amino acid, SS-14 (clinical analogues are made towards SS-14); the 28 amino acid, SS-28; and the 25 amino acid, SS-25 [95]. SS-28 and SS-25 are in fact SS-14 with a 14-amino acid and an 11-amino acid extension at the N-terminus, respectively [96]. SS-14 and SS-28 have similar physiological activities but bind to the receptors with different potencies, while not much is known about SS-25 [95].
SS exerts its effects via five different receptor subtypes (sst1–sst5) that are high-affinity membrane-bound GPCRs and are expressed throughout the CNS and on the pancreas, gut, pituitary, kidneys, thyroid, lung, and endothelial and immune cells [92, 93]. SS affects various tissues and is known to inhibit endocrine and exocrine secretions, intestinal motility, modulate neurotransmission, motor and cognitive functions, vascular contractility, and cell proliferation [92]. All five receptors are known to play a role in the anti-proliferative effect of SS. Binding of SS to sst2 and sst3 leads to apoptosis via p53-independent pathways. On the other hand, binding of SS to sst1, sst2, sst4, and sst5 leads to cytostasis via different pathways including increase of p21Cip1/Waf1, induction of p27Kip1, hypophosphorylation of retinoblastoma (Rb) protein, inhibition of cyclin E/cdk2, inhibition of MAPK cascade, and inhibition of guanylyl cyclase [93]. Additionally, SS also inhibits cellular proliferation by inhibiting secretion of numerous growth factors such as growth hormone, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin-like growth factors I and II (IGF-I and IGF-II), insulin-like growth factor binding protein, and PDGF [93].
11 Somatostatin and Angiogenesis
In contrast to all the aforementioned neuropeptides, one of the earliest studies investigating the role of SS on vasculature suggested that SS decreases blood flow in the gut [96]. Later on it was suggested that this was a direct effect of SS on vascular smooth muscle cells [97]. It is now known that the vasomodulatory effects of SS are confined to the splanchnic circulation and that SS decreases gut motility most likely by causing the release of vasoconstrictors such as endothelin-1 [98].
SS as an anti-angiogenic peptide has a therapeutic potential in the treatment of diseases such as cancer, proliferative retinopathy, and endometriosis where the goal is to inhibit angiogenesis. Using a chick embryo-chorioallantoic membrane (CAM) assay, Woltering and colleagues conducted one of the first studies indicating a role for SS as an anti-angiogenic neuropeptide, suggesting a role for SS in tumor angiogenesis [99].
sst2 is the most commonly involved receptor eliciting the anti-angiogenic effects of SS along with sst1 and sst5. SS is shown to have anti-angiogenic effect by suppressing the expression of pro-angiogenic factors such as VEGF and VEGFR2 [100], IGF-R1, and angiopoietin 2 (Ang 2) and its receptor Tie-2 [101] or by increasing the expression of anti-angiogenic factors such as thrombospondin-1 (TSP-1) [102].
The antitumor effect of SS could be direct by leading to tumor cell apoptosis or indirect by suppressing angiogenesis and inhibiting growth factors [103]. sst2 is commonly involved in cancers. Over-expression of sst2 in human pancreatic (capan-2) and lung cancer cells (A549) transplanted in mice inhibited the growth of both sst2-positive and sst2-negative xenografts by affecting the cellular levels of signaling molecules in apoptotic pathways, MAPK pathway, and angiogenesis [104]. SS analogue, octreotide, has been therapeutically used in cancer treatment, especially neuroendocrine tumors [105–107]. Octreotide has also shown beneficial effects in a mouse hepatocellular carcinoma model where it inhibited the incidence of second primary tumors, decreased lung metastasis, and prolonged the life span by decreasing intratumoral angiogenesis [108]. In a gastric cancer trial, compared to patients that received placebo, patients that received SS had significant decrease in serum VEGF level, which was partially dependent on the synthesis and degradation of the protein but not the transcription of mRNA [109]. SS treatment has also demonstrated beneficial effects in prostate cancer, pancreatic adenocarcinoma models, and an ovarian cancer study [110–113].
In addition to cancer treatment, SS analogues are used for the treatment of refractory bleeding in gastrointestinal angiodysplasias [111, 114] and have also shown beneficial effects in models of endometriosis where receptors sst1, sst2, and sst5 are highly expressed [115]. SS is also used in treatment of proliferative retinopathy [116, 117] where another SS receptor agonist, non-peptide imidazolidine-2,4-dione (NISA), similar to octreotide, inhibited growth factor-induced EC proliferation, migration, and tube formation [118].
Unlike the other neuropeptides discussed, SS is the only one that is proven to be anti-angiogenic and the only one that has been successfully used as an anti-angiogenic agent in cancers. In addition, these data demonstrate that SS-based therapy can also be promising in the treatment of other diseases such as proliferative retinopathy and endometriosis.
12 Conclusions
Neuropeptides have a tremendous potential to be developed as therapies for treating myriads of diseases in which modulation of angiogenesis is essential. Thus in ischemia and impaired wound healing, therapies should aim at enhancing NPY, SP, CGRP, and VIP signaling and to inhibit SS signaling system (Fig. 4.1). Conversely in cancer, the goal ought to be to block the NPY, SP, CGRP, and VIP signaling system and to enhance SS signaling (Fig. 4.1). At time there is lack of in-depth understanding regarding the signaling mechanisms of some neuropeptides therefore, the common and overlapping pathways through which some of these neuropeptides signal should be further explored for their potential therapeutic use. Another area that needs investigation is delivery of neuropeptides, their analogues or receptor antagonists at the disease site. For example, one of the challenges in treating chronic wounds such as diabetic foot ulcers is that the wound microenvironment is very hostile with high expression of proteases, and therefore direct application of neuropeptides to the wound site is not feasible. Another example is in treatment of ischemic revascularization where a systemic delivery of neuropeptide and/or analogue is necessary. One way to overcome this problem is by inhibiting proteases that could cause endogenous neuropeptide degradation instead of systemic injection of neuropeptides that is not feasible. One such protease, neprilysin, that breaks down substance P has already received some attention. However, this too could pose a problem because systemic increase of neuropeptides has a high potential for side effects as these neuropeptides participate in several different physiological processes.
Overall, neuropeptides play an important role in angiogenesis and their ubiquitous nature emphasizes that they can affect angiogenesis in almost all organs. Thus further in-depth exploration is necessary to develop neuropeptide-based angiogenesis therapies and develop strategies for their efficacious delivery.
References
Hulagu S, Senturk O, Erdem A et al (2002) Effects of losartan, somatostatin and losartan plus somatostatin on portal hemodynamics and renal functions in cirrhosis. Hepatogastroenterology 49:783–787
Ruohonen ST, Abe K, Kero M et al (2009) Sympathetic nervous system-targeted neuropeptide Y overexpression in mice enhances neointimal formation in response to vascular injury. Peptides 30:715–720
Kuo LE, Abe K, Zukowska Z (2007) Stress, NPY and vascular remodeling: implications for stress-related diseases. Peptides 28:435–440
Abe K, Tilan JU, Zukowska Z (2007) NPY and NPY receptors in vascular remodeling. Curr Top Med Chem 7:1704–1709
Zukowska Z, Grant DS, Lee EW (2003) Neuropeptide Y: a novel mechanism for ischemic angiogenesis. Trends Cardiovasc Med 13:86–92
Lee EW, Grant DS, Movafagh S et al (2003) Impaired angiogenesis in neuropeptide Y (NPY)-Y2 receptor knockout mice. Peptides 24:99–106
Ejaz A, LoGerfo FW, Pradhan L (2011) Diabetic neuropathy and heart failure: role of neuropeptides. Expert Rev Mol Med 13:e26
Jain M, LoGerfo FW, Guthrie P et al (2011) Effect of hyperglycemia and neuropeptides on interleukin-8 expression and angiogenesis in dermal microvascular endothelial cells. J Vasc Surg 53:1654–1660 e2
Pradhan L, Cai X, Wu S et al (2011) Gene expression of pro-inflammatory cytokines and neuropeptides in diabetic wound healing. J Surg Res 167:336–342
Zhang S, Liu Y, Guo S et al (2010) Vasoactive intestinal polypeptide relaxes isolated rat pulmonary artery rings through two distinct mechanisms. J Physiol Sci 60:389–397
Blomqvist AG, Herzog H (1997) Y-receptor subtypes—how many more? Trends Neurosci 20:294–298
Adrian TE, Allen JM, Bloom SR et al (1983) Neuropeptide Y distribution in human brain. Nature 306:584–586
Fried G, Terenius L, Hokfelt T et al (1985) Evidence for differential localization of noradrenaline and neuropeptide Y in neuronal storage vesicles isolated from rat vas deferens. J Neurosci 5:450–458
Ekblad E, Edvinsson L, Wahlestedt C et al (1984) Neuropeptide Y co-exists and co-operates with noradrenaline in perivascular nerve fibers. Regul Pept 8:225–235
Zukowska Z, Pons J, Lee EW et al (2003) Neuropeptide Y: a new mediator linking sympathetic nerves, blood vessels and immune system? Can J Physiol Pharmacol 81:89–94
Brothers SP, Wahlestedt C (2010) Therapeutic potential of neuropeptide Y (NPY) receptor ligands. EMBO Mol Med 2:429–439
Franco-Cereceda A, Lundberg JM, Dahlof C (1985) Neuropeptide Y and sympathetic control of heart contractility and coronary vascular tone. Acta Physiol Scand 124:361–369
Erlinge D, Brunkwall J, Edvinsson L (1994) Neuropeptide Y stimulates proliferation of human vascular smooth muscle cells: cooperation with noradrenaline and ATP. Regul Pept 50:259–265
Zukowska-Grojec Z, Pruszczyk P, Colton C et al (1993) Mitogenic effect of neuropeptide Y in rat vascular smooth muscle cells. Peptides 14:263–268
Bedoui S, Kawamura N, Straub RH et al (2003) Relevance of neuropeptide Y for the neuroimmune crosstalk. J Neuroimmunol 134:1–11
Pedrazzini T, Pralong F, Grouzmann E (2003) Neuropeptide Y: the universal soldier. Cell Mol Life Sci 60:350–377
Zukowska-Grojec Z, Karwatowska-Prokopczuk E, Rose W et al (1998) Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium. Circ Res 83:187–195
Kohno D, Gao HZ, Muroya S et al (2003) Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin. Diabetes 52:948–956
Ejaz A, LoGerfo FW, Khabbaz K et al (2011) Expression of neuropeptide Y, substance P, and their receptors in the right atrium of diabetic patients. Clin Transl Sci 4:346–450
Robich MP, Matyal R, Chu LM et al (2010) Effects of neuropeptide Y on collateral development in a swine model of chronic myocardial ischemia. J Mol Cell Cardiol 49:1022–1030
Zatelli MC, Minoia M, Martini C et al (2010) Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids. Endocr Relat Cancer 17:719–729
Lee EW, Michalkiewicz M, Kitlinska J et al (2003) Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles. J Clin Invest 111:1853–1862
Movafagh S, Hobson JP, Spiegel S et al (2006) Neuropeptide Y induces migration, proliferation, and tube formation of endothelial cells bimodally via Y1, Y2, and Y5 receptors. FASEB J 20:1924–1926
Ackermann PW, Ahmed M, Kreicbergs A (2002) Early nerve regeneration after Achilles tendon rupture—a prerequisite for healing? A study in the rat. J Orthop Res 20:849–856
Ekstrand AJ, Cao R, Bjorndahl M et al (2003) Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing. Proc Natl Acad Sci U S A 100:6033–6038
Lu C, Everhart L, Tilan J et al (2010) Neuropeptide Y and its Y2 receptor: potential targets in neuroblastoma therapy. Oncogene 29:5630–5642
Lenkinski RE, Bloch BN, Liu F et al (2008) An illustration of the potential for mapping MRI/MRS parameters with genetic over-expression profiles in human prostate cancer. MAGMA 21:411–421
Kitlinska J, Abe K, Kuo L et al (2005) Differential effects of neuropeptide Y on the growth and vascularization of neural crest-derived tumors. Cancer Res 65:1719–1728
Hokfelt T, Kellerth JO, Nilsson G et al (1975) Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neurons. Brain Res 100:235–252
Maggi CA (2000) The troubled story of tachykinins and neurokinins. Trends Pharmacol Sci 21:173–175
Pradhan L, Nabzdyk C, Andersen ND et al (2009) Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev Mol Med 11:e2
Maggi CA (1995) The mammalian tachykinin receptors. Gen Pharmacol 26:911–944
Nieber K, Oehme P (1982) [Substance P—a neuropeptide transmitter]. Z Gesamte Inn Med 37:577–582
Nilsson J, von Euler AM, Dalsgaard CJ (1985) Stimulation of connective tissue cell growth by substance P and substance K. Nature 315:61–63
Ziche M, Morbidelli L, Pacini M et al (1990) Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc Res 40:264–278
Rameshwar P, Poddar A, Zhu G et al (1997) Receptor induction regulates the synergistic effects of substance P with IL-1 and platelet-derived growth factor on the proliferation of bone marrow fibroblasts. J Immunol 158:3417–3424
Khawaja AM, Rogers DF (1996) Tachykinins: receptor to effector. Int J Biochem Cell Biol 28:721–738
Harrison S, Geppetti P (2001) Substance p. Int J Biochem Cell Biol 33:555–576
Delgado AV, McManus AT, Chambers JP (2003) Production of tumor necrosis factor-alpha, interleukin 1-beta, interleukin 2, and interleukin 6 by rat leukocyte subpopulations after exposure to substance P. Neuropeptides 37:355–361
Chu JM, Chen LW, Chan YS et al (2011) Neuroprotective effects of neurokinin receptor one in dopaminergic neurons are mediated through Akt/PKB cell signaling pathway. Neuropharmacology 61:1389–1398
Bulut K, Felderbauer P, Deters S et al (2008) Sensory neuropeptides and epithelial cell restitution: the relevance of SP- and CGRP-stimulated mast cells. Int J Colorectal Dis 23:535–541
Felderbauer P, Bulut K, Hoeck K et al (2007) Substance P induces intestinal wound healing via fibroblasts—evidence for a TGF-beta-dependent effect. Int J Colorectal Dis 22:1475–1480
Couture R, Gaudreau P, St-Pierre S et al (1980) The dog common carotid artery: a sensitive bioassay for studying vasodilator effects of substance P and of kinins. Can J Physiol Pharmacol 58:1234–1244
Persson MG, Hedqvist P, Gustafsson LE (1991) Nerve-induced tachykinin-mediated vasodilation in skeletal muscle is dependent on nitric oxide formation. Eur J Pharmacol 205:295–301
Gustafsson LE, Wiklund CU, Wiklund NP et al (1990) Modulation of autonomic neuroeffector transmission by nitric oxide in guinea pig ileum. Biochem Biophys Res Commun 173:106–110
Amadesi S, Reni C, Katare R et al (2012) Role for substance P-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects. Circulation 125(14):1774–1786
Andersson G, Backman LJ, Scott A et al (2011) Substance P accelerates hypercellularity and angiogenesis in tendon tissue and enhances paratendinitis in response to Achilles tendon overuse in a tendinopathy model. Br J Sports Med 45:1017–1022
Munoz M, Covenas R (2010) Neurokinin-1 receptor: a new promising target in the treatment of cancer. Discov Med 10:305–313
Munoz M, Rosso M, Covenas R (2011) The NK-1 receptor: a new target in cancer therapy. Curr Drug Targets 12:909–921
Wiedermann CJ, Auer B, Sitte B et al (1996) Induction of endothelial cell differentiation into capillary-like structures by substance P. Eur J Pharmacol 298:335–338
Kohara H, Tajima S, Yamamoto M et al (2010) Angiogenesis induced by controlled release of neuropeptide substance P. Biomaterials 31:8617–8625
Scott JR, Muangman P, Gibran NS (2007) Making sense of hypertrophic scar: a role for nerves. Wound Repair Regen 15(suppl 1):S27–S31
Burssens P, Steyaert A, Forsyth R et al (2005) Exogenously administered substance P and neutral endopeptidase inhibitors stimulate fibroblast proliferation, angiogenesis and collagen organization during Achilles tendon healing. Foot Ankle Int 26:832–839
Khare VK, Albino AP, Reed JA (1998) The neuropeptide/mast cell secretagogue substance P is expressed in cutaneous melanocytic lesions. J Cutan Pathol 25:2–10
Singh D, Joshi DD, Hameed M et al (2000) Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis. Proc Natl Acad Sci U S A 97:388–393
Harford-Wright E, Lewis KM, Vink R (2011) Towards drug discovery for brain tumours: interaction of kinins and tumours at the blood brain barrier interface. Recent Pat CNS Drug Discov 6:31–40
Munoz M, Covenas R (2011) NK-1 receptor antagonists: a new paradigm in pharmacological therapy. Curr Med Chem 18:1820–1831
Munoz M, Rosso M, Robles-Frias MJ et al (2010) 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. Lab Invest 90:1259–1269
Mayordomo C, Garcia-Recio S, Ametller E et al (2012) Targeting of substance P induces cancer cell death and decreases the steady state of EGFR and Her2. J Cell Physiol 227:1358–1366
Adeghate E, Ponery A (2003) Pancreatic peptides, neuropeptides and neurotransmitters in diabetes mellitus: a review. Int J Diabetes Metab 11:1–6
Bergdahl A, Valdemarsson S, Nilsson T et al (1999) Dilatory responses to acetylcholine, calcitonin gene-related peptide and substance P in the congestive heart failure rat. Acta Physiol Scand 165:15–23
McLatchie LM, Fraser NJ, Main MJ et al (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–339
van Rossum D, Hanisch UK, Quirion R (1997) Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 21:649–678
Walker CS, Conner AC, Poyner DR et al (2010) Regulation of signal transduction by calcitonin gene-related peptide receptors. Trends Pharmacol Sci 31:476–483
Brain SD, Williams TJ, Tippins JR et al (1985) Calcitonin gene-related peptide is a potent vasodilator. Nature 313:54–56
Gardiner SM, Compton AM, Kemp PA et al (1991) Haemodynamic effects of human alpha-calcitonin gene-related peptide following administration of endothelin-1 or NG-nitro-L-arginine methyl ester in conscious rats. Br J Pharmacol 103:1256–1262
Manek S, Terenghi G, Shurey C et al (1993) Neovascularisation precedes neural changes in the rat groin skin flap following denervation: an immunohistochemical study. Br J Plast Surg 46:48–55
Manek S, Terenghi G, Shurey C et al (1994) Angiogenesis and reinnervation in skin flaps: the effects of ischaemia examined in an animal model. Int J Exp Pathol 75:243–255
Mapp PI, McWilliams DF, Turley MJ et al (2012) A role for the sensory neuropeptide calcitonin gene-related peptide in endothelial cell proliferation in vivo. Br J Pharmacol 166:1261–1271
Zheng S, Li W, Xu M et al (2010) Calcitonin gene-related peptide promotes angiogenesis via AMP-activated protein kinase. Am J Physiol Cell Physiol 299:C1485–C1492
Toda M, Suzuki T, Hosono K et al (2008) Roles of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis. Biomed Pharmacother 62:352–359
Ohno T, Hattori Y, Komine R et al (2008) Roles of calcitonin gene-related peptide in maintenance of gastric mucosal integrity and in enhancement of ulcer healing and angiogenesis. Gastroenterology 134:215–225
Toda M, Suzuki T, Hosono K et al (2008) Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide. Proc Natl Acad Sci U S A 105:13550–13555
White CM, Ji S, Cai H et al (2010) Therapeutic potential of vasoactive intestinal peptide and its receptors in neurological disorders. CNS Neurol Disord Drug Targets 9:661–666
Gaw AJ, Aberdeen J, Humphrey PP et al (1991) Relaxation of sheep cerebral arteries by vasoactive intestinal polypeptide and neurogenic stimulation: inhibition by L-NG-monomethyl arginine in endothelium-denuded vessels. Br J Pharmacol 102:567–572
Guan CX, Cui YR, Sun GY et al (2009) Role of CREB in vasoactive intestinal peptide-mediated wound healing in human bronchial epithelial cells. Regul Pept 153:64–69
Wollina U, Huschenbeck J, Knoll B et al (1997) Vasoactive intestinal peptide supports induced migration of human keratinocytes and their colonization of an artificial polyurethane matrix. Regul Pept 70:29–36
Wollina U, Knopf B (1993) Vasoactive-intestinal-peptide (vip) modulates early events of migration in human keratinocytes. Int J Oncol 2:229–232
Marion-Audibert AM, Nejjari M, Pourreyron C et al (2000) [Effects of endocrine peptides on proliferation, migration and differentiation of human endothelial cells]. Gastroenterol Clin Biol 24:644–648
Yang J, Zong CH, Zhao CH et al (2009) [Vasoactive intestinal peptide enhances angiogenesis after focal cerebral ischemia]. Nan Fang Yi Ke Da Xue Xue Bao 29:619–622
Yang J, Zong CH, Zhao ZH et al (2009) Vasoactive intestinal peptide in rats with focal cerebral ischemia enhances angiogenesis. Neuroscience 161:413–421
Zhao Z, Cheng Q, Li X et al (2006) [c-fos antisense oligodeoxynucleotide reduces VIP-induced upregulation of VEGF expression in small cell lung cancer cells]. Zhongguo Fei Ai Za Zhi 9:312–315
Collado B, Carmena MJ, Clemente C et al (2007) Vasoactive intestinal peptide enhances growth and angiogenesis of human experimental prostate cancer in a xenograft model. Peptides 28:1896–1901
Collado B, Sanchez MG, Diaz-Laviada I et al (2005) Vasoactive intestinal peptide (VIP) induces c-fos expression in LNCaP prostate cancer cells through a mechanism that involves Ca2+ signalling. Implications in angiogenesis and neuroendocrine differentiation. Biochim Biophys Acta 1744:224–233
Ogasawara M, Murata J, Kamitani Y et al (1999) Inhibition by vasoactive intestinal polypeptide (VIP) of angiogenesis induced by murine colon 26-L5 carcinoma cells metastasized in liver. Clin Exp Metastasis 17:283–291
Brazeau P, Vale W, Burgus R et al (1974) Isolation of somatostatin (a somatotropin release inhibiting factor) of ovine hypothalamic origin. Can J Biochem 52:1067–1072
Ferjoux G, Bousquet C, Cordelier P et al (2000) Signal transduction of somatostatin receptors negatively controlling cell proliferation. J Physiol Paris 94:205–210
Dasgupta P (2004) Somatostatin analogues: multiple roles in cellular proliferation, neoplasia, and angiogenesis. Pharmacol Ther 102:61–85
Shulkes A (1994) Somatostatin: physiology and clinical applications. Baillieres Clin Endocrinol Metab 8:215–236
McIntosh CH, Bakich V, Kwok YN et al (1986) A comparison of the inhibitory effects of somatostatin-14, -25, and -28 on motility of the guinea pig ileum. Can J Physiol Pharmacol 64:303–306
Koch H (1976) [Gastrointestinal hormones and blood circulation in the gastric mucosa]. Z Gastroenterol 14(suppl):105–109
Tyden G, Samnegard H, Thulin L et al (1979) Circulatory effects of somatostatin in anesthetized man. Acta Chir Scand 145:443–446
Huang HC, Lee FY, Chan CC et al (2002) Effects of somatostatin and octreotide on portal-systemic collaterals in portal hypertensive rats. J Hepatol 36:163–168
Woltering EA, Barrie R, O’Dorisio TM et al (1991) Somatostatin analogues inhibit angiogenesis in the chick chorioallantoic membrane. J Surg Res 50:245–251
Bocci G, Culler MD, Fioravanti A et al (2007) In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists. Eur J Clin Invest 37:700–708
Dal Monte M, Cammalleri M, Martini D et al (2007) Antiangiogenic role of somatostatin receptor 2 in a model of hypoxia-induced neovascularization in the retina: results from transgenic mice. Invest Ophthalmol Vis Sci 48:3480–3489
Laklai H, Laval S, Dumartin L et al (2009) Thrombospondin-1 is a critical effector of oncosuppressive activity of sst2 somatostatin receptor on pancreatic cancer. Proc Natl Acad Sci U S A 106:17769–17774
Hasskarl J, Kaufmann M, Schmid HA (2011) Somatostatin receptors in non-neuroendocrine malignancies: the potential role of somatostatin analogs in solid tumors. Future Oncol 7:895–913
Zhou T, Xiao X, Xu B et al (2009) Overexpression of SSTR2 inhibited the growth of SSTR2-positive tumors via multiple signaling pathways. Acta Oncol 48:401–410
Faivre S, Sablin MP, Dreyer C et al (2010) Novel anticancer agents in clinical trials for well-differentiated neuroendocrine tumors. Endocrinol Metab Clin North Am 39:811–826
Valentino J, Evers BM (2011) Recent advances in the diagnosis and treatment of gastrointestinal carcinoids. Adv Surg 45:285–300
Florio T (2008) Molecular mechanisms of the antiproliferative activity of somatostatin receptors (SSTRs) in neuroendocrine tumors. Front Biosci 13:822–840
Jia WD, Xu GL, Wang W et al (2009) A somatostatin analogue, octreotide, inhibits the occurrence of second primary tumors and lung metastasis after resection of hepatocellular carcinoma in mice. Tohoku J Exp Med 218:155–160
Zhao B, Yang P, Yang J et al (2011) A randomized trial of somatostatin to regulate the VEGFs/VEGFRs in patients with gastric cancer. Hepatogastroenterology 58:1425–1430
Sun LC, Luo J, Mackey LV et al (2007) A conjugate of camptothecin and a somatostatin analog against prostate cancer cell invasion via a possible signaling pathway involving PI3K/Akt, alphaVbeta3/alphaVbeta5 and MMP-2/-9. Cancer Lett 246:157–166
Kumar M, Liu ZR, Thapa L et al (2004) Anti-angiogenic effects of somatostatin receptor subtype 2 on human pancreatic cancer xenografts. Carcinogenesis 25:2075–2081
Hall GH, Turnbull LW, Bedford K et al (2005) Neuropilin-1 and VEGF correlate with somatostatin expression and microvessel density in ovarian tumours. Int J Oncol 27:1283–1288
Carrere N, Vernejoul F, Souque A et al (2005) Characterization of the bystander effect of somatostatin receptor sst2 after in vivo gene transfer into human pancreatic cancer cells. Hum Gene Ther 16:1175–1193
Molina-Infante J, Perez-Gallardo B (2011) Somatostatin analogues for bleeding gastrointestinal angiodysplasias: when should thalidomide be prescribed? Dig Dis Sci 56:266–267
Fasciani A, Quilici P, Biscaldi E et al (2010) Overexpression and functional relevance of somatostatin receptor-1, -2, and -5 in endometrium and endometriotic lesions. J Clin Endocrinol Metab 95:5315–5319
Prokosch V, Fink J, Heiduschka P et al (2011) VEGF, Ang-2 and SRIF associated abnormal postnatal development of the retinal capillary network in the Royal College of Surgeons rat. Exp Eye Res 92:128–137
Simo R, Carrasco E, Garcia-Ramirez M et al (2006) Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev 2:71–98
Palii SS, Afzal A, Shaw LC et al (2008) Nonpeptide somatostatin receptor agonists specifically target ocular neovascularization via the somatostatin type 2 receptor. Invest Ophthalmol Vis Sci 49:5094–5102
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Pradhan-Nabzdyk, L., Nabzdyk, C. (2013). Neuropeptides and Angiogenesis. In: Mehta, J., Dhalla, N. (eds) Biochemical Basis and Therapeutic Implications of Angiogenesis. Advances in Biochemistry in Health and Disease, vol 6. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5857-9_4
Download citation
DOI: https://doi.org/10.1007/978-1-4614-5857-9_4
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-5856-2
Online ISBN: 978-1-4614-5857-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)