scholarly journals eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Takeshi Ninchoji ◽  
Dominic T Love ◽  
Ross O Smith ◽  
Marie Hedlund ◽  
Dietmar Vestweber ◽  
...  
Keyword(s):  
No Synthase ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Ocular Diseases ◽  
Oxygen Induced Retinopathy ◽  
No Formation ◽  
Therapy Development ◽  
Endothelial Growth Factor ◽  
Deutsche Forschungsgemeinschaft

Background:Hypoxia and consequent production of vascular endothelial growth factor A (VEGFA) promote blood vessel leakiness and edema in ocular diseases. Anti-VEGFA therapeutics may aggravate hypoxia; therefore, therapy development is needed.Methods:Oxygen-induced retinopathy was used as a model to test the role of nitric oxide (NO) in pathological neovascularization and vessel permeability. Suppression of NO formation was achieved chemically using L-NMMA, or genetically, in endothelial NO synthase serine to alanine (S1176A) mutant mice.Results:Suppression of NO formation resulted in reduced retinal neoangiogenesis. Remaining vascular tufts exhibited reduced vascular leakage through stabilized endothelial adherens junctions, manifested as reduced phosphorylation of vascular endothelial (VE)-cadherin Y685 in a c-Src-dependent manner. Treatment with a single dose of L-NMMA in established retinopathy restored the vascular barrier and prevented leakage.Conclusions:We conclude that NO destabilizes adheren junctions, resulting in vascular hyperpermeability, by converging with the VEGFA/VEGFR2/c-Src/VE-cadherin pathway.Funding:This study was supported by the Swedish Cancer foundation (19 0119 Pj ), the Swedish Research Council (2020-01349), the Knut and Alice Wallenberg foundation (KAW 2020.0057) and a Fondation Leducq Transatlantic Network of Excellence Grant in Neurovascular Disease (17 CVD 03). KAW also supported LCW with a Wallenberg Scholar grant (2015.0275). WCS was supported by Grants R35 HL139945, P01 HL1070205, AHA MERIT Award. DV was supported by grants from the Deutsche Forschungsgemeinschaft, SFB1450, B03, and CRU342, P2.

scholarly journals eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin

2020 ◽  
Author(s):  
Takeshi Ninchoji ◽  
Dominic T. Love ◽  
Ross O. Smith ◽  
Marie Hedlund ◽  
Dietmar Vestweber ◽  
...  
Keyword(s):  
Adherens Junctions ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Oxygen Induced Retinopathy ◽  
No Formation ◽  
Intervention Treatment ◽  
Oxide Synthase ◽  
Endothelial Growth Factor ◽  
Endothelial Nitric Oxide

AbstractHypoxia and the production of vascular endothelial growth factor A (VEGFA) promote blood vessel leakiness and edema in ocular diseases. Therapeutics targeting VEGFA suppress leakiness and edema but aggravate hypoxia; therefore, new therapeutics are needed. We examined the role of endothelial nitric oxide synthase (eNOS) in pathological neovascularization and vessel permeability during oxygen-induced retinopathy. NO formation was suppressed chemically using L-NMMA, or genetically, in eNOS serine to alanine (S1176A) mutant mice, resulting in reduced retinal neoangiogenesis. Both strategies resulted in reduced vascular leakage by stabilizing endothelial adherens junctions through suppressed phosphorylation of vascular endothelial (VE)-cadherin Y685 in a c-Src-dependent manner. Intervention treatment by a single dose of L-NMMA in established retinopathy restored the vascular barrier and prevented leakage. We conclude that eNOS induces destabilization of adherens junctions and vascular hyperpermeability by converging with the VEGFA/VEGFR2/c-Src/VE-cadherin pathway and that this pathway can be selectively inhibited by blocking NO formation.

scholarly journals Intraocular injection of KH902 alleviates retinal hypoxia in a mouse model of oxygen-induced retinopathy

2021 ◽  
pp. 38-38
Author(s):  
Ning Yang ◽  
Xuejun He ◽  
Ningzhi Zhang ◽  
Yiqiao Xing
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Mouse Model ◽  
Vascular Endothelial ◽  
Ocular Diseases ◽  
Vegf Expression ◽  
Pathological Angiogenesis ◽  
Intraocular Injection ◽  
Oxygen Induced Retinopathy ◽  
Endothelial Growth Factor

Inhibition of vascular endothelial growth factor (VEGF) has been widely applied in antineovascularization therapies. As a novel anti-VEGF agent, KH902 (conbercept) is designed to restrain pathological angiogenesis. However, the effects of KH902 on retinal hypoxia have not been well studied. In a mouse model of oxygen-induced retinopathy (OIR), we assessed retinal hypoxia at postnatal days 14 (P14) and P17, as well as retinal neovascularization (RNV) at P17. In addition, we evaluated the protein level of VEGF and galectin-1 (Gal-1). Changes of the neuroretinal structure were also examined. Our results indicated that KH902 could remit retinal hypoxia in OIR at P14 and P17, which was an exciting novel finding for KH902 function. Additionally, we confirmed that KH902 markedly reduces RNV. Our results indicated that administration of KH902 downregulated VEGF expression, as well as Gal-1. Damage of neuroretinal structure after KH902 injection was not observed, which was also an encouraging result. Our study suggests that KH902 plays a role in alleviating retinal hypoxia and that it could be used for the treatment of other neovascular ocular diseases.

scholarly journals Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin αvβ3

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 2015-2026 ◽  
Author(s):  
Sribalaji Lakshmikanthan ◽  
Magdalena Sobczak ◽  
Changzoon Chun ◽  
Angela Henschel ◽  
Jillian Dargatz ◽  
...  
Keyword(s):  
Integrin Αvβ3 ◽  
In Vivo Model ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Kinase Activation ◽  
Vegf Signaling ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF) acting through VEGF receptor 2 (VEGFR2) on endothelial cells (ECs) is a key regulator of angiogenesis, a process essential for wound healing and tumor metastasis. Rap1a and Rap1b, 2 highly homologous small G proteins, are both required for angiogenesis in vivo and for normal EC responses to VEGF. Here we sought to determine the mechanism through which Rap1 promotes VEGF-mediated angiogenesis. Using lineage-restricted Rap1-knockout mice we show that Rap1-deficiency in endothelium leads to defective angiogenesis in vivo, in a dose-dependent manner. Using ECs obtained from Rap1-deficient mice we demonstrate that Rap1b promotes VEGF-VEGFR2 kinase activation and regulates integrin activation. Importantly, the Rap1b-dependent VEGF-VEGFR2 activation is in part mediated via integrin αvβ3. Furthermore, in an in vivo model of zebrafish angiogenesis, we demonstrate that Rap1b is essential for the sprouting of intersomitic vessels, a process known to be dependent on VEGF signaling. Using 2 distinct pharmacologic VEGFR2 inhibitors we show that Rap1b and VEGFR2 act additively to control angiogenesis in vivo. We conclude that Rap1b promotes VEGF-mediated angiogenesis by promoting VEGFR2 activation in ECs via integrin αvβ3. These results provide a novel insight into the role of Rap1 in VEGF signaling in ECs.

scholarly journals HIF-1α stabilization modified by glutaredoxin-1 is critical for intestinal angiogenesis in NEC pathogenesis

2021 ◽  
Author(s):  
Yunfei Zhang ◽  
Xiao Zhang ◽  
Bing Tian ◽  
Qin Deng ◽  
Chunbao Guo
Keyword(s):  
Hypoxia Inducible Factor ◽  
Capillary Density ◽  
Current Data ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Intestinal Tissue ◽  
Intestinal Microcirculation ◽  
Endothelial Growth Factor ◽  
Predetermined Time

Abstract Background: Hypoxia inducible factor (HIF-1α) are essential in the pathogenesis of necrotizing enterocolitis (NEC), which is stabilized by Grx1 deletion. Until now, the mechanism of HIF-1α in the intestinal microcirculation in NEC is not well defined. We intend to investigate the role of HIF-1α in the development of NEC in regulating the microcirculation and the following vasodilatory signal, VEGF. Materials and methods: Experimental NEC was induced in full-term C57BL/6 mouse and Grx1-/-pups through the formula gavage and hypoxia technique. The HIF-1α signal was blocked utilizing the HIF-1α inhibitor, YC-1. Intestinal tissues were collected at predetermined time points for the assessment of intestinal microcirculation and the HIF-1α activity involved signal. Results: We found that NEC inducement impaired the intestinal microcirculation, but intestinal blood flow and capillary density were ameliorated in Grx1-/-mice, which was associated with the GSH-protein adducts of HIF-1α in the intestinal tissue. Grx1 ablation could also promote vascular endothelial growth factor (VEGFA) production in the intestinal tissue. This intestinal microvascular improvement was not found in the HIF-1α inhibited mice, suggesting the HIF-1α dependent manner for intestinal microcirculatory perfusion. Conclusion: The current data demonstrated that HIF-1α signaling is involved in the intestinal microvascular modification during the pathogenesis of NEC, suggesting that targeting with HIF-1α might be a promising strategy for NEC treatment.

scholarly journals HIF-1α stabilization modified by glutaredoxin-1 is critical for intestinal angiogenesis in NEC pathogenesis

2021 ◽  
Author(s):  
Yunfei Zhang ◽  
Xiao Zhang ◽  
Bing Tian ◽  
Xionghui Ding ◽  
Cuilian Ye ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Capillary Density ◽  
Current Data ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Intestinal Tissue ◽  
Intestinal Microcirculation ◽  
Endothelial Growth Factor ◽  
Predetermined Time

AbstractBackgroundHypoxia inducible factor (HIF-1α) are essential in the pathogenesis of necrotizing enterocolitis (NEC), which is stabilized by Grx1 deletion. Until now, the mechanism of HIF-1α in the intestinal microcirculation in NEC is not well defined. We intend to investigate the role of HIF-1α in the development of NEC in regulating the microcirculation and the following vasodilatory signal, VEGF.Materials and methodsExperimental NEC was induced in full-term C57BL/6 mouse and Grx1-/- pups through the formula gavage and hypoxia technique. The HIF-1α signal was blocked utilizing the HIF-1α inhibitor, YC-1. Intestinal tissues were collected at predetermined time points for the assessment of intestinal microcirculation and the HIF-1α activity involved signal.ResultsWe found that NEC inducement impaired the intestinal microcirculation, but intestinal blood flow and capillary density were ameliorated in Grx1-/- mice, which was associated with the GSH-protein adducts of HIF-1α in the intestinal tissue. Grx1 ablation could also promote vascular endothelial growth factor (VEGFA) production in the intestinal tissue. This intestinal microvascular improvement was not found in the HIF-1α inhibited mice, suggesting the HIF-1α dependent manner for intestinal microcirculatory perfusion.ConclusionThe current data demonstrated that HIF-1α signaling is involved in the intestinal microvascular modification during the pathogenesis of NEC, suggesting that targeting with HIF-1α might be a promising strategy for NEC treatment.

scholarly journals Angiotensin II stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes

2006 ◽  
Vol 36 (2) ◽  
pp. 377-388 ◽  
Author(s):  
Young Sun Kang ◽  
Yun Gyu Park ◽  
Bo Kyung Kim ◽  
Sang Youb Han ◽  
Yi Hwa Jee ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Ang Ii ◽  
Vegf Mrna ◽  
Mitogen Activated Protein ◽  
Endothelial Growth Factor

Angiotensin II (Ang-II) and vascular endothelial growth factor (VEGF) have an important role in the pathogenesis of diabetic nephropathy, but the signaling cascade of VEGF regulation in response to Ang-II in podocytes is largely unknown. In these experiments, we looked at the effect of Ang-II on the production of VEGF, and investigated whether VEGF production depends on the p38 mitogen activated protein kinase (MAPK) pathway in cultured mouse podocytes. Incubation of podocytes with Ang-II induced a rapid increase in VEGF mRNA expression and protein synthesis as well as its transcriptional activity in an Ang-II dose-dependent manner. To further define the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors involved in Ang-II-mediated VEGF synthesis, the effects of selective AT1 and AT2 receptor antagonists were evaluated. Prior treatment with losartan significantly inhibited VEGF mRNA and protein synthesis induced by Ang-II, which suggests that the AT1 receptor is involved in Ang-II-mediated VEGF synthesis. Furthermore, stimulation of the cells with Ang-II increased both phosphorylation of p38 MAPK and MAP kinase kinase 3/6 (MKK3/6). Additionally, Ang-II enhanced the DNA binding activity to cAMP response element binding protein (CREB) and phosphorylation of CREB. In addition, to investigate the role of p38 MAPK in Ang-II-induced VEGF synthesis, podocytes were pretreated with or without the p38 MAPK inhibitor, SB203580 for 24 h to observe whether Ang-II-mediated VEGF synthesis was inhibited by blocking p38 MAPK. The addition of SB203580 led to a marked inhibition of the increased VEGF mRNA and protein production induced by Ang-II in a dose-dependent manner. Taken together, these results suggest that Ang-II stimulates the synthesis of VEGF in podocytes and the production of VEGF induced by Ang-II is mediated, in part, through the activation of the p38 MAPK pathway.

scholarly journals Manipulation of Quercetin and Melatonin in the Down-Regulation of HIF-1α, HSP-70 and VEGF Pathways in Rat’s Kidneys Induced by Hypoxic Stress

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582094979
Author(s):  
Aliah R. Alshanwani ◽  
Sameerah Shaheen ◽  
Laila M. Faddah ◽  
Ahlam M. Alhusaini ◽  
Hanaa M. Ali ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Histopathological Examination ◽  
Hemoglobin Concentration ◽  
Vascular Endothelial ◽  
Hsp 70 ◽  
Reactive Protein ◽  
Defensive Role ◽  
Factor Α ◽  
Endothelial Growth Factor

Hypoxia may lead to inflammatory responses by numerous signaling pathways. This investigation intended to inspect the defensive role of Quercetin (Quer) and/ or Melatonin (Mel) against reno toxicity induced by Sodium nitrite (Sod ntr). Sod ntr injection significantly decreased blood hemoglobin concentration (Hb) with a concurrent increase in serum tumor necrosis factor- α, interleukin-6, C-reactive protein, creatinine, and urea levels. Over protein-expression of vascular endothelial growth factor and heat shock, protein-70 and mRNA of HIF-1α were also observed. Pretreatment of the Sod ntr- injected rats with the aforementioned antioxidants; either alone or together significantly improved such parameters. Histopathological examination reinforced the previous results. It was concluded that the combined administration of Quer and Mel may be useful as a potential therapy against renal injury induced by Sod ntr. HIF-1α and HSP-70 are implicated in the induction of hypoxia and its treatment.

scholarly journals New insights on the role of vascular endothelial growth factor in biliary pathophysiology

JHEP Reports ◽  
2021 ◽  
Vol 3 (3) ◽  
pp. 100251
Author(s):  
Valeria Mariotti ◽  
Romina Fiorotto ◽  
Massimiliano Cadamuro ◽  
Luca Fabris ◽  
Mario Strazzabosco
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor
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