Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophages are supposed to play a key role in inflammatory and tumor angiogenesis. Their importance derives from (1) their ubiquitous presence in normal and especially inflamed tissues, (2) their potential to become activated in response to appropriate stimuli, and (3) their repertoire of secretory products. By release of proteases, growth factors (bFGF, GM-CSF, TGF-alpha, IGF-I, PDGF, VEGF/VPF, TGF-beta), and other monokines (IL-1, IL-6, IL-8, TNF-alpha, substance P, prostaglandins, interferons, thrombospondin 1), activated macrophages have the capability to influence each phase of the angiogenic process, such as alterations of the local extracellular matrix, induction of endothelial cells to migrate or proliferate, and inhibition of vascular growth with formation of differentiated capillaries. This review describes macrophage physiology and the influence of macrophage secretory products on the different phases of angiogenesis in vitro and in vivo.
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PMID:Macrophages and angiogenesis. 750 44

The effects of coronary artery disease (CAD) on human coronary microvascular responses to vascular endothelial growth factor (VEGF) and the alterations of the myocardial expressions of VEGF and its flk-1 and flt-1 receptors were examined in 48 patients. Microvascular studies were performed in vitro with video microscopy. The expressions of VEGF and its receptors were examined using Northern analysis of total mRNA, and the expressions of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) were examined by RT-PCR. VEGF and hepatocyte growth factor (HGF) caused potent relaxations of microvessels. These responses were reduced in the presence of NG-nitro-L-arginine and the tyrosine kinase inhibitor genistein or in microvessels from patients with CAD. Relaxations to substance P and sodium nitroprusside were similar in both groups. The substance P response was abolished in the presence of NG-nitro-L-arginine. The expression of VEGF and its receptors and the expression of cNOS and iNOS were not altered in patients with CAD. In conclusion, VEGF and HGF elicit the release of nitric oxide through activation of tyrosine kinase receptors. CAD is associated with reduced vascular responses to both VEGF and HGF; this is not likely due to a reduced expression of VEGF or flt-1 or flk-1 receptors and not due to a generalized endothelium dysfunction despite the presence of mild hypercholesterolemia in these patients with CAD. These findings may have important implications regarding the efficacy of endogenous and exogenous VEGF in patients with risk factor for CAD.
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PMID:Effects of coronary artery disease on expression and microvascular response to VEGF. 974 92

Inhibition of angiogenesis has been proposed as a novel therapeutic approach to the treatment of chronic inflammatory diseases such as rheumatoid arthritis. We have assessed carrageenan synovitis in male Wistar rats as a potential model of the increased vascular turnover observed in human synovitis. Intra-articular injection of 100 microl of 2% carrageenan in the right knee on Day 0 was followed by acute joint swelling through Day 3 and persistent macrophage infiltration at Day 28. Endothelial cell proliferation and endothelial cell death each peaked during the acute phase and remained elevated during persistent synovitis. Vascular densities were high in normal synovia, decreased during the acute phase, transiently increased at Day 14, and then returned to control values by Day 28. Lower doses of carrageenan, which stimulated acute joint swelling and macrophage infiltration but not endothelial cell proliferation at Day 3, were not associated with persistent macrophage infiltration at Day 28. Intra-articular injection of substance P or vascular endothelial growth factor, angiogenic factors that are present in normal synovia or are up-regulated during inflammation, respectively, each stimulated endothelial cell expression of proliferating cell nuclear antigen. Increased vascular turnover during acute and persistent phases of synovitis may be regulated by different factors and may serve different roles. The late phase (Day 28) of carrageenan synovitis displays similarities with rheumatoid synovitis, in which endothelial cell turnover is persistently increased despite little overall change in vascular density.
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PMID:Vascular turnover during carrageenan synovitis in the rat. 988 51

A permissive role of nitric oxide (NO) in endothelial cell migration and angiogenesis promoted by vascular endothelial growth factor (VEGF), endothelin, and substance P has previously been established. The present studies were designed to examine the mechanism(s) involved in the NO effect on focal adhesions. Time-lapse videomicroscopy of human umbilical vein endothelial cells (HUVECs) plated on the silicone rubber substrate revealed that unstimulated cells were constantly remodeling the wrinkling pattern, indicative of changing tractional forces. Application of NO donors reversibly decreased the degree of wrinkling, consistent with the release of tractional forces exerted by focal adhesions and stress fibers. Morphometric and immunocytochemical analyses showed that NO inhibited adhesion and spreading of HUVECs and attenuated recruitment of paxillin to focal adhesions. NO also had a profound dose-dependent effect on the formation of stress fibers by HUVECs. De novo formation of focal adhesions in HUVECs was significantly diminished in the presence of NO donors. Migration of HUVECs showed an absolute requirement for the functional NO synthase. NO donors did not interfere with focal adhesion kinase recruitment to focal adhesions but affected the state of its tyrosine phosphorylation, as judged from the results of immunoprecipitation and immunoblotting experiments. Videomicroscopy of HUVECs presented with VEGF in a micropipette showed that the rate of cell migration was slowed down by NO synthase inhibition as well as by inhibition of tyrosine phosphorylation. Collectively, these data indicate that NO reversibly releases tractional forces exerted by spreading endothelial cells via interference with the de novo formation of focal adhesions, tyrosine phosphorylation of components of focal adhesion complexes, and assembly of stress fibers.
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PMID:Nitric oxide modulation of focal adhesions in endothelial cells. 1036 89

The aim of this study was to investigate the effects of vascular endothelial growth factor (VEGF) on regeneration of the rat sciatic nerve in vivo. To that end we used 10-mm long cell-free nerve grafts to bridge a gap in the sciatic nerve. The grafts were pretreated with either VEGF (50, 100 or 250 ng/ml), nerve growth factor (NGF, 100 ng/ml) or laminin (100 ng/ml) before implantation. Outgrowth of axons, Schwann cells, blood vessels and macrophages were studied 10 days post-implantation by the use of immunocytochemistry and histochemistry. Grafts pretreated with VEGF stimulated the outgrowth of Schwann cells and blood vessels but not axons. In such grafts, the Schwann cells also exhibited a dramatic change in morphology and became filled with large lipid-containing vacuoles. These cells also showed an intense immunoreactivity for the VEGF receptor flk-1. Neither pretreatment with laminin nor NGF affected the outgrowth of Schwann cells. However, NGF treatment increased the number of axons in the graft but was not able to counteract injury-induced downregulation of substance P in the dorsal root ganglia. The results show that local application of VEGF promotes at least two events, invasion of Schwann cells and neovascularization, which are important during nerve regeneration. The findings suggest that the effects of the pretreatment by the growth factors is local and limited to the graft, whereas central events like neuropeptide synthesis is not affected.
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PMID:Vascular endothelial growth factor stimulates Schwann cell invasion and neovascularization of acellular nerve grafts. 1055 39

Angiogenesis and microvascular remodeling are known features of chronic inflammatory diseases such as asthma and chronic bronchitis, but the mechanisms and consequences of the changes are just beginning to be elucidated. In a model of chronic airway inflammation produced by Mycoplasma pulmonis infection of the airways of mice or rats, angiogenesis and microvascular remodeling create vessels that mediate leukocyte influx and leak plasma proteins into the airway mucosa. These vascular changes are driven by the immune response to the organisms. Plasma leakage results from gaps between endothelial cells, as well as from increased vascular surface area and probably other changes in the newly formed and remodeled blood vessels. Treatment with long-acting beta2 agonists can reduce but not eliminate the plasma occurring after infection. In addition to the elevated baseline leakage, the remodeled vessels in the airway mucosa are abnormally sensitive to substance P, but not to platelet-activating factor or serotonin, suggesting that the infection leads to a selective upregulation of NK1 receptors on the vasculature. The formation of new vessels and the remodeling of existing vessels are likely to be induced by multiple growth factors, including vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang1). VEGF increases vascular permeability, but Ang1 has the opposite effect. This feature is consistent with evidence that VEGF and Ang1 play complementary and coordinated roles in vascular growth and remodeling and have powerful effects on vascular function. Regulation of vascular permeability by VEGF and Ang1 may be their most rapid and potent actions in the adult, as these effects can occur independent of their effects on angiogenesis and vascular remodeling. The ability of Ang1 to block plasma leakage without producing angiogenesis may be therapeutically advantageous. Furthermore, because VEGF and Ang1 have additive effects in promoting angiogenesis but opposite effects on vascular permeability, they could be used together to avoid the formation of leaky vessels in therapeutic angiogenesis. Finally, the elucidation of the protective effect of Ang1 on blood vessel leakiness to plasma proteins raises the possibility of a new strategy for reducing airway edema in inflammatory airway diseases such as asthma and chronic bronchitis.
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PMID:Angiogenesis and remodeling of airway vasculature in chronic inflammation. 1173 65

We examined the utility of herpes simplex virus (HSV) vector-mediated gene transfer of vascular endothelial growth factor (VEGF) in a mouse model of diabetic neuropathy. A replication-incompetent HSV vector with VEGF under the control of the HSV ICP0 promoter (vector T0VEGF) was constructed. T0VEGF expressed and released VEGF from primary dorsal root ganglion (DRG) neurons in vitro, and following subcutaneous inoculation in the foot, expressed VEGF in DRG and nerve in vivo. At 2 weeks after induction of diabetes, subcutaneous inoculation of T0VEGF prevented the reduction in sensory nerve amplitude characteristic of diabetic neuropathy measured 4 weeks later, preserved autonomic function measured by pilocarpine-induced sweating, and prevented the loss of nerve fibers in the skin and reduction of neuropeptide calcitonin gene-related peptide and substance P in DRG neurons of the diabetic mice. HSV-mediated transfer of VEGF to DRG may prove useful in treatment of diabetic neuropathy.
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PMID:HSV-mediated gene transfer of vascular endothelial growth factor to dorsal root ganglia prevents diabetic neuropathy. 1592 Apr 61

Mast cells are critical players in allergic reactions, but they have also been shown to be important in immunity and recently also in inflammatory diseases, especially asthma. Migraines are episodic, typically unilateral, throbbing headaches that occur more frequently in patients with allergy and asthma implying involvement of meningeal and/or brain mast cells. These mast cells are located perivascularly, in close association with neurons especially in the dura, where they can be activated following trigeminal nerve, as well as cervical or sphenopalatine ganglion stimulation. Neuropeptides such as calcitonin gene-related peptide (CGRP), hemokinin A, neurotensin (NT), pituitary adenylate cyclase activating peptide (PACAP), and substance P (SP) activate mast cells leading to secretion of vasoactive, pro-inflammatory, and neurosensitizing mediators, thereby contributing to migraine pathogenesis. Brain mast cells can also secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), selectively in response to corticotropin-releasing hormone (CRH), a mediator of stress which is known to precipitate or exacerbate migraines. A better understanding of brain mast cell activation in migraines would be useful and could lead to several points of prophylactic intervention.
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PMID:The role of mast cells in migraine pathophysiology. 1596 Sep 87

This study was conducted to identify bone resorption and anti-inflammatory effects with intermittent cyclical etidronate therapy (ICET) in patients with rheumatoid arthritis, and anti-inflammatory effect of etidronate in vitro. We compared bone mineral density (BMD), urinary deoxypyridinoline (DPD) level, bone alkaline phosphatase (BAP) level and Larsen damage scores between the ICET and the non-ICET groups for 3 years. The levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2), substance P and vascular endothelial growth factor (VEGF) in synovial cells from arthritis models were measured following the addition of etidronate. In the ICET group, BMD and BAP levels increased. Urinary DPD level and the Larsen damage score were significantly lower than that in the non-ICET group. In the in vitro study, the production of IL-6, PGE2, substance P and VEGF were inhibited in a dose-dependent manner. Bone resorption and destruction inhibition effect of etidronate remained for 3 years. In vitro study showed that the production of inflammatory cytokines and an angiogenesis factor were inhibited.
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PMID:Inhibitory effect of bone resorption and inflammation with etidronate therapy in patients with rheumatoid arthritis for 3 years and in vitro assay in arthritis models. 1613 81

Denervation degrades normal ligament properties and impairs ligament healing. This suggests that secreted neuromediators, such as neuropeptides, could be modulating cell metabolism in ligament and scar tissue. To test this hypothesis we investigated the effect of exogenous substance P (SP), neuropeptide Y (NPY) or calcitonin gene-related peptide (CGRP) on the mRNA levels for proteins associated with inflammation, angiogenesis, and matrix production in tissue-cultured specimens of normal and injured medial collateral ligament. SP and NPY induced increased mRNA levels for several inflammatory mediators in the 2-week post-injury specimens. All three neuropeptides induced decreases in mRNA levels for healing-associated growth factors and matrix molecules, including basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and collagen types I and III. The results indicate that neuropeptides strongly influence the metabolic activity of cells in healing ligament, particularly at early time points after injury.
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PMID:Neuropeptides regulate expression of matrix molecule, growth factor and inflammatory mediator mRNA in explants of normal and healing medial collateral ligament. 1729 90


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