scholarly journals Neutrophils and Macrophages Promote Angiogenesis in the Early Stage of Endometriosis in a Mouse Model

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1278-1286 ◽  
Author(s):  
Yiu-Jiuan Lin ◽  
Ming-Derg Lai ◽  
Huan-Yao Lei ◽  
Lih-Yuh C. Wing
Keyword(s):  
Mouse Model ◽  
Blood Vessels ◽  
Immune Cells ◽  
Early Stage ◽  
Treated Group ◽  
Ectopic Tissue ◽  
Ovariectomized Mice ◽  
Inflammatory Protein ◽  
Endothelial Growth Factor

Substantial evidence suggests that inflammatory cytokines, immune cells, and angiogenesis are important for endometriosis. In this study, we investigated the role of the sequential events in the development of endometriosis in a mouse model. Uterine tissue was transplanted into the peritoneum of ovariectomized mice and then supplemented with estrogen or vehicle. On different days after transplantation, cell proliferation, angiogenesis, and infiltrated immune cells in ectopic tissue were examined using immunochemical staining. Many disintegrated blood vessels but no bromodeoxyuridine-positive cells in ectopic tissue were observed in the estrogen-treated group on posttransplantation d 1 and 2. On d 4–7, bromodeoxyuridine-positive cells were detected in the blood vessels of ectopic tissue, indicating that angiogenesis was initiated in this stage. Angiogenesis also occurred in ectopic tissue in the vehicle-treated group. Profound infiltration of neutrophils in ectopic tissue occurred on d 1–4, when the number of neutrophils and levels of macrophage inflammatory protein (MIP)-1α and MIP-2 chemokines in peritoneal fluids also reached their peak. Peritoneal macrophage numbers did not change, but secretions of TNFα, IL-6, MIP-1α, and MIP-2 from macrophages isolated on d 2 were higher than on d 0. In vitro studies showed that peritoneal neutrophils and macrophages secreted vascular endothelial growth factor, which was up-regulated by TNFα and IL-6. Our results suggest that neutrophils and macrophages may promote angiogenesis in the early stage of endometriosis and that chemokines and cytokines amplify the angiogenic signal for the growth of endometriotic tissue.

scholarly journals Phospholipase Cγ Activation Drives Increased Production of Autotaxin in Endothelial Cells and Lysophosphatidic Acid-Dependent Regression

2010 ◽  
Vol 30 (10) ◽  
pp. 2401-2410 ◽  
Author(s):  
Eunok Im ◽  
Ruta Motiejunaite ◽  
Jorge Aranda ◽  
Eun Young Park ◽  
Lorenzo Federico ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Lysophosphatidic Acid ◽  
Vascular Endothelial ◽  
Additional Mechanism ◽  
Phospholipase Cγ1 ◽  
Common Substrate ◽  
Phosphoinositide 3 Kinase ◽  
Endothelial Growth Factor

ABSTRACT We previously reported that vascular endothelial growth factor (VEGF)-dependent activation of phospholipase Cγ1 (PLCγ) regulated tube stability by competing with phosphoinositide 3-kinase (PI3K) for their common substrate. Here we describe an additional mechanism by which PLCγ promoted regression of tubes and blood vessels. Namely, it increased the level of autotaxin (ATX), which is a secreted form of lysophospholipase D that produces lysophosphatidic acid (LPA). LPA promoted motility of endothelial cells, leading to disorganization/regression of tubes in vitro. Furthermore, mice that under- or overexpressed members of this intrinsic destabilization pathway showed either delayed or accelerated, respectively, regression of blood vessels. We conclude that endothelial cells can be instructed to engage a PLCγ-dependent intrinsic destabilization pathway that results in the production of soluble regression factors such as ATX and LPA. These findings are likely to potentiate ongoing efforts to prevent, manage, and eradicate numerous angiogenesis-based diseases such as proliferative diabetic retinopathy and solid tumors.

scholarly journals A Novel Piperazine-Based Drug Lead for Cryptosporidiosis from the Medicines for Malaria Venture Open-Access Malaria Box

2018 ◽  
Vol 62 (4) ◽  
pp. e01505-17 ◽  
Author(s):  
R. S. Jumani ◽  
K. Bessoff ◽  
M. S. Love ◽  
P. Miller ◽  
E. E. Stebbins ◽  
...  
Keyword(s):  
Mouse Model ◽  
Drug Development ◽  
Early Stage ◽  
New Drugs ◽  
Cryptosporidium Hominis ◽  
Content Type ◽  
Knockout Mouse Model ◽  
Malaria Box

ABSTRACTCryptosporidiosis causes life-threatening diarrhea in children under the age of 5 years and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to the need for new drugs, better knowledge of drug properties that drivein vivoefficacy is needed to facilitate drug development. We report the identification of a piperazine-based lead compound forCryptosporidiumdrug development, MMV665917, and a new pharmacodynamic method used for its characterization. The identification of MMV665917 from the Medicines for Malaria Venture Malaria Box was followed by dose-response studies,in vitrotoxicity studies, and structure-activity relationship studies using commercial analogues. The potency of this compound againstCryptosporidium parvumIowa and field isolates was comparable to that againstCryptosporidium hominis. Furthermore, unlike nitazoxanide, clofazimine, and paromomycin, MMV665917 appeared to be curative in a NOD SCID gamma mouse model of chronic cryptosporidiosis. MMV665917 was also efficacious in a gamma interferon knockout mouse model of acute cryptosporidiosis. To determine if efficacy in this mouse model of chronic infection might relate to whether compounds are parasiticidal or parasitistatic forC. parvum, we developed a novelin vitroparasite persistence assay. This assay suggested that MMV665917 was parasiticidal, unlike nitazoxanide, clofazimine, and paromomycin. The assay also enabled determination of the concentration of the compound required to maximize the rate of parasite elimination. This time-kill assay can be used to prioritize early-stageCryptosporidiumdrug leads and may aid in planningin vivoefficacy experiments. Collectively, these results identify MMV665917 as a promising lead and establish a new method for characterizing potential anticryptosporidial agents.

scholarly journals Three-Dimensional In Vitro Staphylococcus aureus Abscess Communities Display Antibiotic Tolerance and Protection from Neutrophil Clearance

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Marloes I. Hofstee ◽  
Martijn Riool ◽  
Igors Terjajevs ◽  
Keith Thompson ◽  
Martin J. Stoddart ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Cells ◽  
Early Stage ◽  
Three Dimensional ◽  
Collagen Gel ◽  
Maximum Size ◽  
Human Neutrophils ◽  
Content Type

ABSTRACT Staphylococcus aureus is a prominent human pathogen in bone and soft-tissue infections. Pathophysiology involves abscess formation, which consists of central staphylococcal abscess communities (SACs), surrounded by a fibrin pseudocapsule and infiltrating immune cells. Protection against the ingress of immune cells such as neutrophils, or tolerance to antibiotics, remains largely unknown for SACs and is limited by the lack of availability of in vitro models. We describe a three-dimensional in vitro model of SACs grown in a human plasma-supplemented collagen gel. The in vitro SACs reached their maximum size by 24 h and elaborated a fibrin pseudocapsule, as confirmed by electron and immunofluorescence microscopy. The in vitro SACs tolerated 100× the MIC of gentamicin alone and in combination with rifampin, while planktonic controls and mechanically dispersed SACs were efficiently killed. To simulate a host response, SACs were exposed to differentiated PLB-985 neutrophil-like (dPLB) cells and to primary human neutrophils at an early stage of SAC formation or after maturation at 24 h. Both cell types were unable to clear mature in vitro SACs, but dPLB cells prevented SAC growth upon early exposure before pseudocapsule maturation. Neutrophil exposure after plasmin pretreatment of the SACs resulted in a significant decrease in the number of bacteria within the SACs. The in vitro SAC model mimics key in vivo features, offers a new tool to study host-pathogen interactions and drug efficacy assessment, and has revealed the functionality of the S. aureus pseudocapsule in protecting the bacteria from host phagocytic responses and antibiotics.

scholarly journals S100a8/S100a9-Emmprin-Vegfa Axis Initiated By Tet2-Deficient Immune Cells Exacerbates Lung Cancer Progression through Promotion of Angiogenesis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3276-3276
Author(s):  
Yen T. M. Nguyen ◽  
Manabu Fujisawa ◽  
Tran B. Nguyen ◽  
Yasuhito Suehara ◽  
Tatsuhiro Sakamoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Blood Vessels ◽  
Cancer Progression ◽  
Immune Cells ◽  
Gene Set Enrichment Analysis ◽  
Human Lung Cancer ◽  
Clonal Hematopoiesis ◽  
Deficient Group

Abstract Introductions: Loss-of-function TET2 mutations are frequent in clonal hematopoiesis in patients with solid cancers as well as that in healthy individuals. It remains to be elucidated whether and how TET2-mutated immune cells affect cancer progression in patients with TET2-mutated clonal hematopoiesis. Here, we assessed activity of Tet2-deficient immune cells using a mouse lung cancer model. Methods: Lewis Lung Carcinoma (LLC) cells were subcutaneously transplanted into blood-specific Mx-Cre or myeloid-specific LysM-Cre x Tet2 f/f mice (Tet2 -/- or Tet2 mye-) or control mice (CT). Single-cell RNA sequencing (scRNA-seq) was performed to determine the immune-cell profiles and mediators in tumors of Tet2 -/- mice (Tet2 -/- tumors). Whole transcriptome analysis (WTA) was also performed for granulocytic myeloid-derived cells (GMD), monocytic myeloid-derived cells (MMD), and tumor associated macrophages (TAM), as well as LLC cells sorted from Tet2 -/- tumors and CT tumors. Results: We found that tumor growth was enhanced in both Tet2 -/- and Tet2 mye- comparing to CT. Unsupervised clustering of scRNA-seq data identified 14 cell clusters: GMD into 3 (GMD1, GMD2, and GMD3), MMD into 5 (MMD1, MMD2, MMD3, MMD4, and MMD5), TAMs into 4 (TAM1, TAM2, TAM3, and TAM4), and DCs into 2 (DC1 and DC2). Notably, among all subclusters, the proportions of GMD1, GMD3, TAM3 and TAM4 were markedly expanded in Tet2 -/- tumors comparing to CT. Differentially expressed gene (DEG) analysis of scRNA-seq data found that S100a8 and S100a9 were highly expressed in Tet2-deficient GMD1 compared to CT. Furthermore, S100a8/S100a9 proteins were elevated in plasmas of Tet2 -/- comparing to those of CT. Pathway analysis using DEGs (p < 0.05) from WTA of GMD determined interleukin 1b (Il1b) signaling as upstream of S100a8/S100a9 activity. Gene set enrichment analysis (GSEA) also showed that 6 pathways related to Il1b were enriched in Tet2-deficient group compared to CT group. Gene ontology analysis (GO) for DEGs of GMD, MMD, and TAMs by WTA as well as 13 subclusters by scRNA-seq revealed that the "cellular response to IL-1" pathway was enriched in Tet2-deficient group compared to CT group. To define the downstream effectors in LLC cells, we performed WTA for LLC cells sorted from Tet2 -/- and CT tumors. We found that Vegfa, encoding a mediator for angiogenesis was highly upregulated in LLC cells sorted from Tet2 -/- tumors comparing to CT tumors. GSEA for WTA further identified that multiple Vegfa-related pathways as well as MAPK cascade were enriched in LLC cells from Tet2 -/- tumors comparing to those from CT tumors . Furthermore, S100a8/S100a9 induced Vegfa secretion from LLC cells in vitro. Remarkably, the area of blood vessels was increased in Tet2 -/- tumors comparing to CT tumors. Immunostaining exhibited that the number of Ly6g +GMD foci (>1000 px 2) expressing S100a8/S100a9 was increased in Tet2 -/- tumors comparing to CT tumors. Furthermore, LLC cells surrounding GMD foci highly expressed Vegfa in Tet2 -/- tumors. Finally, administration of an antibody against Emmprin, a receptor for S100a8/S100a9 inhibited the tumor growth in Tet2 -/-. Notably, the area of blood vessels in Tet2 -/- tumors with anti-Emmprin group was decreased at 2-fold compared to that seen in isotype group (p < 0.05). Consistently, S100A8/S100A9 induced VEGFA production in human lung cancer cells in vitro. Conclusions: Tet2-deificient immune cells promote lung cancer progression through S100a8/S100a9-Emmprin-Vegfa axis. Our study suggests a novel role of TET2-mutated clonal hematopoiesis in cancer progression and even provides a novel therapeutic target. Disclosures No relevant conflicts of interest to declare.

scholarly journals Interleukin-37b inhibits the growth of murine endometriosis-like lesions by regulating proliferation, invasion, angiogenesis and inflammation

2020 ◽  
Vol 26 (4) ◽  
pp. 240-255
Author(s):  
Yongpei He ◽  
Ting Xiong ◽  
Fang Guo ◽  
Zhenzhen Du ◽  
Yixian Fan ◽  
...  
Keyword(s):  
Early Stage ◽  
Inflammatory Factors ◽  
Epithelial Cell Line ◽  
Vascular Endothelial ◽  
Gynecological Disease ◽  
Endothelial Growth Factor ◽  
In Vitro Treatment

Abstract Endometriosis is a gynecological disease with abnormal expression of interleukin (IL)-37 which can suppress inflammation and the immune system. Here we investigated the role of the IL-37b splice variant in endometriosis in vivo and in vitro. In a murine model of endometriosis, in vivo administration of IL-37b significantly inhibited the development of lesions judged by the number (P = 0.0213), size (P = 0.0130) and weight (P = 0.0152) of lesions. IL-37b had no effect on the early stage of lesion formation, however administration in the growth stage of lesions decreased the number (P = 0.0158), size (P = 0.0158) and weight (P = 0.0258) of lesions compared with PBS control, an effect that was not reversed by macrophage depletion. Expressions of inflammatory factors, matrix metalloproteinases and vascular endothelial growth factor-A mRNA/protein were significantly inhibited in ectopic lesions following IL-37b administration, and in uterine segments treated in vitro. In vitro treatment of uterine segments with IL-37b inhibited phosphorylation of Akt and Erk1/2 in uterine segments. Isolated mouse endometrial stromal treated with IL-37b and transfected with pIL-37b plasmid got suppressed cell proliferation, invasion, angiogenesis and the expression of inflammatory factors. In addition, transfection with pIL-37b significantly decreased the phosphorylation of Akt and Erk1/2. IL-37b also inhibited proliferation and the expression of inflammatory and angiogenesis factors in epithelial cell line RL95–2. These findings suggest that IL-37b may inhibit the growth of lesions by regulating proliferation, invasion, angiogenesis and inflammation through Akt and Erk1/2 signaling pathway.

scholarly journals Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice

2017 ◽  
Vol 114 (40) ◽  
pp. 10719-10724 ◽  
Author(s):  
Kerstin Berer ◽  
Lisa Ann Gerdes ◽  
Egle Cekanaviciute ◽  
Xiaoming Jia ◽  
Liang Xiao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Autoimmune Disease ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Immune Cells ◽  
Disease Incidence ◽  
Transgenic Mouse Model ◽  
Microbial Composition ◽  
Multiple Sclerosis Patients

There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the CNS. Here, we compared the gut microbial composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial profiles, we found a significant increase in some taxa such as Akkermansia in untreated MS twins. Furthermore, most notably, when transplanted to a transgenic mouse model of spontaneous brain autoimmunity, MS twin-derived microbiota induced a significantly higher incidence of autoimmunity than the healthy twin-derived microbiota. The microbial profiles of the colonized mice showed a high intraindividual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence. These findings provide evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS.

Adenosine A2A Receptor Agonist Mediated Prevention of Graft-Versus Host Disease In the Mouse Is Associated with An Increase of T-Regulatory Cells In Target Organs.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3744-3744
Author(s):  
Kyu Lee Han ◽  
Sherry Walker ◽  
Harry L. Malech ◽  
Elizabeth M. Kang
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Acute Gvhd ◽  
T Regulatory Cells ◽  
Treated Group ◽  
Regulatory Cells ◽  
High Power Field ◽  
Target Organs ◽  
A2ar Agonist

Abstract Abstract 3744 Graft versus host disease (GVHD) is a serious complication of allogenic hematopoietic stem cell transplantation (HSCT) affecting primarily the liver, intestine, skin and lymphoid organs. T-regulatory cells (Tregs) are a subset of T cells that are characterized by CD4+CD25high and express the Foxp3 transcription factor. There is increasing recognition that Tregs likely are important in preventing development, reducing the severity and/or mediating resolution of GVHD. It has been reported that giving donor Tregs will suppress development of GVHD in a mouse model; however it is not clear whether the immunologic suppression by Tregs occurs in the target organs. Agonists of the Gs-coupled Adenosine A2A receptor (A2AR) agonists have been demonstrated to terminate inflammation and improve survival in solid organ transplant ischemia models. We previously have reported that the A2AR specific agonist, ATL146e, also can decrease the incidence and severity of GVHD as well as improve survival of mice in a GVHD transplant mouse model. In this same GVHD mouse model, ATL146e treatment increases the number of donor derived CD4+CD25highFoxp3+ Tregs. In order to further understand the role of the agonist in GVHD abrogation we performed studies looking at A2AR agonist mediated appearance of Tregs in the target organs affected by GVHD in this model. Using a parental into irradiated F1 offspring transplant model (C57BL/6J [B6, H-2b] -> B6D2F1/J [BDF1, H-2b/d]) we can induce GVHD as manifested by weight loss and mortality in 100% of mice by infusing an additional 10 million donor T cells into mice previously engrafted with 10 million bone marrow donor cells using 850cGy conditioning. We administered the A2AR specific agonists, ATL1223 or ATL370, or a PBS control by osmotic mini pumps resulting in continuous subcutaneous infusion for 14 days starting one day before the donor T cell infusion. Mice that received only the donor bone marrow transplant and not the additional donor T cells did not develop GVHD and served as an additional control. We collected ear and colon biopsies from the transplanted mice to assess these target organs (skin and gut) usually affected by GVHD in this model. Tissue was obtained, placed in 10% formalin and paraffin embedded and stained by immunohistochemistry (IHC) for intracellular FoxP3 by incubating overnight with 1:200 mouse anti-mouse/human/rat—FoxP3 IgG. The slides were washed and then incubated with anti-mouse IgG conjugated to Tetramethylrhodamine (TRITC). We then counted the number of Foxp3+ cells per high power field. We also examined whether specific agonist activation of A2AR can increase the number of Tregs in vitro by culturing CD4+ CD25− cells in the presence of either TGF-beta and/or the A2AR specific agonists. As in our previous studies with the specific A2AR agonist ATL146e, the agonists ATL1223 and ATL370 also were effective at preventing the acute GVHD syndrome of weight loss and mortality seen in the PBS treated controls. Treatment with these agonists resulted in an increase in CD4+CD25+FoxP3+ Tregs in the spleen compared to the PBS treated group at days 14 to 20 after HSCT. In addition we were able to document significant increases in the number of Foxp3 positive T lymphocytes infiltrating skin and colon compared to the PBS treated group. The number of Foxp3+ T cells per high power field was 14 ± 6 in the control and 64 ± 14 in the A2AR agonist treated mice (p = 0.0281). Finally from our in vitro data we also observed a 4.2 to 5.4 fold increase in the number of Foxp3+ Tregs in vitro after A2AR activation compared to TGF beta treatment only. Thus we have confirmed that the specific activation of A2AR inhibits acute GVHD through the increase of donor-derived CD4+ CD25+ FoxP3+ immunosuppressive T regulatory cells in vivo and in vitro. Furthermore, our histological observation suggests the possibility that increased Tregs by treatment with A2AR specific agonist is responsible for suppressing the immune response in GVHD target tissues. Therefore, our observation provides additional mechanistic basis for the anti-inflammatory capacity of A2AR agonist in acute GVHD. Additional studies are ongoing to further elucidate the mechanism by which A2AR specific agonist increases Tregs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Novel Pyrazolopyrimidine Derivatives as Tyrosine Kinase Inhibitors with Antitumoral Activity in Vitro and in Vivo in Papillary Dedifferentiated Thyroid Cancer

Endocrinology ◽  
2011 ◽  
Vol 152 (1) ◽  
pp. 334-334 ◽  
Author(s):  
Alessandro Antonelli ◽  
Guido Bocci ◽  
Concettina La Motta ◽  
Silvia Martina Ferrari ◽  
Poupak Fallahi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Line ◽  
Kinase Inhibitors ◽  
Treated Group ◽  
Simultaneous Increase ◽  
Antitumoral Activity ◽  
Proliferation Assays ◽  
Endothelial Growth Factor

Aim: We have studied the antitumoral activity of two new pyrazolo[3,4-d]pyrimidine compounds (CLM3 and CLM29) in primary papillary dedifferentiated thyroid cancer cells (DePTC cells). Methods: The antiproliferative effect was tested in DePTC cells obtained at reoperation from patients with recurrence of the tumor. The concentrations of CLM3 and CLM29 used in the in vitro experiments were 1, 10, 30, and 50 μm. Results: Proliferation assays in DePTC cells showed a significant reduction of proliferation by CLM3 and CLM29, which was by 12% with CLM3 (the most potent compound) 10 μm, 43% with CLM3 30 μm, and 60% with CLM3 50 μm. CLM3 and CLM29 increased the percentage of apoptotic cells in DePTC cells dose dependently (P < 0.001) and inhibited migration (P < 0.001). A DePTC cell line (AL) was injected sc in CD nu/nu mice, and tumor masses became detectable 10 d after xenotransplantation. CLM3 (40 mg/kg·die) significantly inhibited tumor growth and weight, and the therapeutic effect was significant starting on the 19th day after cell implantation (4 d after the beginning of treatment). The CLM3-treated group of animals did not show any appreciable toxicity. CLM3 and CLM29 increased thrombospondin-1 expression in the AL cell line. A significant reduction of microvessels and in the percentage of antivascular endothelial growth factor antibody immunoreactivity was observed in the CLM3 treated tumors, with a simultaneous increase of the percentage of necrosis. Conclusion: The antitumoral activity of two new pyrazolo[3,4-d]pyrimidine compounds (CLM3, CLM29) in vitro and CLM3 in vivo in DePTC has been shown, opening the way to a future clinical evaluation.

VEGF promotes vascular sympathetic innervation

2008 ◽  
Vol 294 (6) ◽  
pp. H2646-H2652 ◽  
Author(s):  
Stephen B. Marko ◽  
Deborah H. Damon
Keyword(s):  
Blood Vessels ◽  
Sympathetic Innervation ◽  
Nerve Fibers ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Sympathetic Nerve Fibers ◽  
Endothelial Growth Factor ◽  
Immunohistochemical Analyses

The sympathetic nervous system, via postganglionic innervation of blood vessels and the heart, is an important determinant of cardiovascular function. The mechanisms underlying sympathetic innervation of targets are not fully understood. This study tests the hypothesis that target-derived vascular endothelial growth factor (VEGF) promotes sympathetic innervation of blood vessels. Western blot and immunohistochemical analyses indicate that VEGF is produced by vascular cells in arteries and that VEGF receptors are expressed on sympathetic nerve fibers innervating arteries. In vitro, exogenously added VEGF and VEGF produced by vascular smooth muscle cells (VSMCs) in sympathetic neurovascular cocultures inhibited semaphorin 3A (Sema3A)-induced collapse of sympathetic growth cones. In the absence of Sema3A, VEGF and VSMCs also increased growth cone area. These effects were mediated via VEGF receptor 1. In vivo, the neutralization of VEGF inhibited the reinnervation of denervated femoral arteries. These data demonstrate that target-derived VEGF plays a previously unrecognized role in promoting the growth of sympathetic axons.

Sign in / Sign up

Export Citation Format

Share Document