Nitric oxide, VEGF, and VEGFR-2: interactions in activity-induced angiogenesis in rat skeletal muscle

2005 ◽  
Vol 289 (1) ◽  
pp. H336-H343 ◽  
Author(s):  
Malgorzata Milkiewicz ◽  
Olga Hudlicka ◽  
Margaret D. Brown ◽  
Haley Silgram
Keyword(s):  
Nitric Oxide ◽  
Nuclear Antigen ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Capillary Growth ◽  
Capillary Bed ◽  
Endothelial Growth Factor ◽  
Proliferating Cell ◽  
Increased Activity ◽  
Increased Blood Flow

Vascular endothelial growth factor (VEGF) is considered to be important in promotion of capillary growth in skeletal muscles exposed to increased activity. We studied its interactions with nitric oxide (NO) by examining the expression of endothelial NO synthase (NOS), VEGF, and VEGF receptor-2 (VEGFR-2) proteins in relation to capillary growth in rat extensor digitorum longus muscles electrically stimulated for 2, 4, or 7 days with and without NOS inhibition by Nω-nitro-l-arginine (l-NNA, 3 mg/day). Stimulation increased all proteins from 2 days onward, concomitantly with capillary proliferation (labeling for proliferating cell nuclear antigen). Capillary-to-fiber ratio was elevated by 25% after 7 days. Concurrent oral administration of l-NNA did not affect the increase in endothelial NOS but depressed its activity, as shown by increased blood pressure and decreased arteriolar diameters in 2-day-stimulated muscles. NOS inhibition eliminated the increased expression of VEGFR-2 and VEGF proteins in muscles stimulated for 2 and 4 days but not for 7 days. However, it depressed capillary proliferation and the increase in C/F at all time points. We conclude that, in stimulated muscles, NO, generated by activation of neuronal NOS by muscle activity or endothelial NOS by increased blood flow and capillary shear stress, may increase capillary proliferation in the early stages of stimulation through upregulation of VEGFR-2 and VEGF. With longer stimulation, capillary growth appears to require NO, and high levels of VEGF and VEGFR-2 may be contributing to maintenance of the increased capillary bed.

scholarly journals Activated Microvessels Express Vascular Endothelial Growth Factor and Integrin αvβ3 During Focal Cerebral Ischemia

1999 ◽  
Vol 19 (9) ◽  
pp. 1038-1050 ◽  
Author(s):  
Takeo Abumiya ◽  
Jacinta Lucero ◽  
Ji Hoe Heo ◽  
Masafumi Tagaya ◽  
James A. Koziol ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Proliferating Cell Nuclear Antigen ◽  
Focal Cerebral Ischemia ◽  
Integrin Αvβ3 ◽  
Nuclear Antigen ◽  
Vascular Endothelial ◽  
Primate Model ◽  
Endothelial Growth Factor ◽  
Proliferating Cell

Both vascular endothelial growth factor (VEGF) and integrin αvβ3 play roles in angiogenesis. In noncerebral vascular systems, VEGF can induce endothelial integrin αvβ3 expression. However, it is unknown whether VEGF, like integrin αvβ3, appears in the initial response of microvessels to focal brain ischemia. Their coordinate expression in microvessels of the basal ganglia after middle cerebral artery occlusion (MCAO) in the nonhuman primate model was examined quantitatively. Cells incorporating deoxyuridine triphosphate (dUTP+) by the polymerase I reaction at 1 hour (n = 3), 2 hours (n = 3), and 7 days (n = 4) after MCAO defined the ischemic core (Ic) and peripheral regions. Both VEGF and integrin αvβ3 were expressed by activated noncapillary (7.5- to 30.0-μm diameter) microvessels in the Ic region at 1 and 2 hours after MCAO. At 7 days after MCAO, the number of VEGF+, integrin αvβ3+, or proliferating cell nuclear antigen-positive microvessels had decreased within the Ic region. The expressions of VEGF, integrin αvβ3, and proliferating cell nuclear antigen were highly correlated on the same microvessels using hierarchical log-linear statistical models. Also, VEGF and subunit αv messenger ribonucleic acids were coexpressed on selected microvessels. Here, noncapillary microvessels are activated specifically early during a focal cerebral ischemic insult and rapidly express VEGF and integrin αvβ3 together.

scholarly journals Vasoactive and Permeability Effects of Vascular Endothelial Growth Factor-165 in the Term in Vitro Dually Perfused Human Placental Lobule

Endocrinology ◽  
2007 ◽  
Vol 148 (10) ◽  
pp. 4734-4744 ◽  
Author(s):  
P. Brownbill ◽  
G. C. McKeeman ◽  
J. C. Brockelsby ◽  
I. P. Crocker ◽  
C. P. Sibley
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Culture Techniques ◽  
Vasodilatory Effect ◽  
Endothelial Growth Factor ◽  
Maternal Side

Vascular endothelial growth factor (VEGF) is an important vasodilator and effector of permeability in systemic blood vessels. Molecular and tissue culture techniques have provided evidence for its placental synthesis and release. Using an in vitro dual-perfusion model of the term placental lobule from normal pregnancy, we report here the relative secretion of total VEGF, soluble VEGF receptor (VEGFR)-1, and free VEGF into the maternal and fetoplacental circulations of the placenta. We tested the hypothesis that VEGF has vasomotor and permeability effects in the fetoplacental circulation of the human placenta, and we examined the broad intracellular pathways involved in the vasodilatory effect that we found. We show that total VEGF is released into the fetal and maternal circulations in a bipolar fashion, with a bias toward maternal side output. Soluble VEGFR-1 was also secreted into both circulations with bias toward the maternal side. Consequently, free VEGF (12.8 ± 2.4 pg/ml, mean ± se) was found only in the fetoplacental circulation. VEGF-165 was found to be a potent vasodilator of the fetoplacental circulation (maximum response: 77% of previous steady-state fetal-side inflow hydrostatic pressure after preconstriction with U46619; EC50 = 71 pm). This vasodilatory effect was mediated by the VEGFR-2 receptor and nitric oxide in a manner-independent of the involvement of prostacyclin and the src-family tyrosine kinases. However, nitric oxide could explain only 50% of the vasodilatory effect. Finally, we measured the permeability of the perfused placenta to inert hydrophilic tracers and found no difference in the presence and absence of VEGF.

Induction of nitric oxide by erythropoietin is mediated by the β common receptor and requires interaction with VEGF receptor 2

Blood ◽  
2010 ◽  
Vol 115 (4) ◽  
pp. 896-905 ◽  
Author(s):  
Larysa Sautina ◽  
Yuri Sautin ◽  
Elaine Beem ◽  
Zhuo Zhou ◽  
Anna Schuler ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Common Receptor ◽  
The Common ◽  
Β Receptor ◽  
And Performance ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF) and erythropoietin (EPO) have profound effects on the endothelium and endothelial progenitor cells (EPCs), which originate from the bone marrow and differentiate into endothelial cells. Both EPO and VEGF have demonstrated an ability to increase the number and performance properties of EPCs. EPC behavior is highly dependent on nitric oxide (NO), and both VEGF and EPO can stimulate intracellular NO. EPO can bind to the homodimeric EPO receptor (EPO-R) and the heterodimeric receptor, EPO-R and the common β receptor (βC-R). Although VEGF has several receptors, VEGF-R2 appears most critical to EPC function. We demonstrate that EPO induction of NO is dependent on the βC-R and VEGF-R2, that VEGF induction of NO is dependent on the expression of the βC-R, and that the βC-R and VEGF-R2 interact. This is the first definitive functional and structural evidence of an interaction between the 2 receptors and has implications for the side effects of EPO.

scholarly journals Human dental pulp stem cells attenuate streptozotocin-induced parotid gland injury in rats

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rasha H. Al-Serwi ◽  
Ahmed Othman Fathy Othman El-Kersh ◽  
Gehan El-Akabawy
Keyword(s):  
Nitric Oxide ◽  
Parotid Gland ◽  
Salivary Flow ◽  
Nuclear Antigen ◽  
Vascular Endothelial ◽  
Glucose Levels ◽  
Gland Weight ◽  
Human Dental Pulp ◽  
Oxide Synthase ◽  
Endothelial Growth Factor

Abstract Objective Diabetes mellitus causes deterioration in the body, including serious damage of the oral cavity related to salivary gland dysfunction, characterised by hyposalivation and xerostomia. Human dental pulp stem cells (hDPSCs) represent a promising therapy source, due to the easy, minimally invasive surgical access to these cells and their high proliferative capacity. It was previously reported that the trophic support mediated by these cells can rescue the functional and structural alterations of damaged salivary glands. However, potential differentiation and paracrine effects of hDPSCs in diabetic-induced parotid gland damage have not been investigated. Our study aimed to investigate the therapeutic effects of intravenous transplantation of hDPSCs on parotid gland injury in a rat model of streptozotocin (STZ)-induced type 1 diabetes. Methods Thirty Sprague–Dawley male rats were randomly categorised into three groups: control, diabetic (STZ), and transplanted (STZ + hDPSCs). The hDPSCs or the vehicles were injected into the rats’ tail veins, 7 days after STZ injection. Fasting blood glucose levels were monitored weekly. A glucose tolerance test was performed, and the parotid gland weight, salivary flow rate, oxidative stress indices, parotid gland histology, and caspase-3, vascular endothelial growth factor, proliferating cell nuclear antigen, neuronal nitric oxide synthase, endothelial nitric oxide synthase, and tetrahydrobiopterin biosynthetic enzyme expression levels in parotid tissues were assessed 28 days post-transplantation. Results Transplantation of hDPSCs decreased blood glucose, improved parotid gland weight and salivary flow rate, and reduced oxidative stress. The cells migrated to the STZ-injured parotid gland and differentiated into acinar, ductal, and myoepithelial cells. Moreover, hDPSCs downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and proliferating cell nuclear antigen, likely exerting pro-angiogenic and anti-apoptotic effects and promoting endogenous regeneration. In addition, the transplanted cells enhanced the parotid nitric oxide-tetrahydrobiopterin pathway. Conclusions Our results showed that hDPSCs migrated to and survived within the STZ-injured parotid gland, where functional and morphological damage was prevented due to the restoration of normal glucose levels, differentiation into parotid cell populations, and stimulation of paracrine-mediated regeneration. Thus, hDPSCs may have potential in the treatment of diabetes-induced parotid gland injury.

scholarly journals Establishment of a Model of Microencapsulated SGC7901 Human Gastric Carcinoma Cells Cocultured with Tumor-Associated Macrophages

2018 ◽  
Vol 2018 ◽  
pp. 1-10
Author(s):  
Jin-Ming Zhu ◽  
Xiu-Lian Quan ◽  
Shi-Chao Han ◽  
Xue-Jun Fan ◽  
He-Ming Li ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase 2 ◽  
Nuclear Antigen ◽  
Vascular Endothelial ◽  
Tumor Associated Macrophages ◽  
Successful Establishment ◽  
Endothelial Growth Factor ◽  
Proliferating Cell ◽  
Metalloproteinase 9 ◽  
Human Gastric Carcinoma Cells

The important factors of poor survival of gastric cancer (GC) are relapse and metastasis. For further elucidation of the mechanism, a culture system mimicking the microenvironment of the tumor in humans was needed. We established a model of microencapsulated SGC7901 human GC cells and evaluated the effects of coculturing spheres with tumor-associated macrophages (TAMs). SGC7901 cells were encapsulated in alginate-polylysine-sodium alginate (APA) microcapsules using an electrostatic droplet generator. MTT assays showed that the numbers of microencapsulated cells were the highest after culturing for 14 days. Metabolic curves showed consumption of glucose and production of lactic acid by day 20. Immunocytochemistry confirmed that Proliferating Cell Nuclear Antigen (PCNA) and Vascular Endothelial Growth Factor (VEGF) were expressed in microencapsulated SGC7901 cells on days 7 and 14. The expression of PCNA was observed outside spheroids; however, VEGF was found in the entire spheroids. PCNA and VEGF were increased after being cocultured with TAMs. Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) expressions were detected in the supernatant of microencapsulated cells cocultured with TAMs but not in microencapsulated cells. Our study confirms the successful establishment of the microencapsulated GC cells. TAMs can promote PCNA, VEGF, MMP-2, and MMP-9 expressions of the GC cells.

Aspirin inhibits endothelial nitric oxide synthase (eNOS) and Flk-1 (vascular endothelial growth factor receptor-2) prior to rat colon tumour development

2004 ◽  
Vol 106 (1) ◽  
pp. 83-91 ◽  
Author(s):  
Marta ESCRIBANO ◽  
Laura MOLERO ◽  
Antonio LÓPEZ-FARRÉ ◽  
Cynthia ABARRATEGUI ◽  
Carolina CARRASCO ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Blood Vessels ◽  
Caspase 3 ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Colonic Tissue ◽  
Colon Tumour ◽  
Endothelial Growth Factor

Formation of blood vessels is a fundamental element in the control of tumour growth in which vascular endothelial growth factor (VEGF) and nitric oxide (NO) have been demonstrated to be involved. Our aim was to analyse whether changes in the expression of endothelial NO synthase (eNOS) and VEGF in colonic tissue could be detected early and even before the identification of colon tumour-associated morphological modifications in azoxymethane-treated rats. We studied further whether aspirin treatment changed these parameters. An increased expression of both eNOS and VEGF in colonic tissue from azoxymethane-treated rats compared with that from control rats was found. Aspirin treatment (10 mg/kg of body weight per day) reduced eNOS expression, but failed to modify the expression of VEGF in the colonic tissue of azoxymethane-treated rats. No evidence of aberrant crypt formation or changes in the number of blood vessels were observed in the colon of any of the animals studied. Expression of the VEGF receptor Flk-1, but not Flt-1, was increased in colonic tissue of azoxymethane-treated rats compared with control rats. The expression of Flk-1 was mainly localized in the epithelial cells, particularly in the lower part of the crypt. Aspirin treatment reduced Flk-1 expression in both control and azoxymethane-treated rats. Caspase-3 activity, which has been considered as an apoptotic index, was almost undetectable in azoxymethane-treated rats. Aspirin treatment stimulated caspase-3 activity. Overexpression of eNOS, VEGF and its receptor Flk-1 occurred early after azoxymethane administration in rat colonic tissue, even before morphological changes associated with tumour generation were observed, and aspirin prevented the overexpression of both eNOS and VEGF receptor Flk-1.

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