scholarly journals Regulation of neovascularization by S-glutathionylation via the Wnt5a/sFlt-1 pathway

2014 ◽  
Vol 42 (6) ◽  
pp. 1665-1670 ◽  
Author(s):  
Colin E. Murdoch ◽  
Markus M. Bachschmid ◽  
Reiko Matsui
Keyword(s):  
Actin Polymerization ◽  
Network Formation ◽  
Nuclear Factor Κb ◽  
Capillary Density ◽  
Vascular Endothelial ◽  
Retinal Blood Vessel ◽  
Recovery Exercise ◽  
Vessel Development ◽  
Cysteine Thiols ◽  
Endothelial Growth Factor

S-glutathionylation occurs when reactive oxygen or nitrogen species react with protein-cysteine thiols. Glutaredoxin-1 (Glrx) is a cytosolic enzyme which enzymatically catalyses the reduction in S-glutathionylation, conferring reversible signalling function to proteins with redox-sensitive thiols. Glrx can regulate vascular hypertrophy and inflammation by regulating the activity of nuclear factor κB (NF-κB) and actin polymerization. Vascular endothelial growth factor (VEGF)-induced endothelial cell (EC) migration is inhibited by Glrx overexpression. In mice overexpressing Glrx, blood flow recovery, exercise function and capillary density were significantly attenuated after hindlimb ischaemia (HLI). Wnt5a and soluble Fms-like tyrosine kinase-1 (sFlt-1) were enhanced in the ischaemic-limb muscle and plasma respectively from Glrx transgenic (TG) mice. A Wnt5a/sFlt-1 pathway had been described in myeloid cells controlling retinal blood vessel development. Interestingly, a Wnt5a/sFlt-1 pathway was found also to play a role in EC to inhibit network formation. S-glutathionylation of NF-κB components inhibits its activation. Up-regulated Glrx stimulated the Wnt5a/sFlt-1 pathway through enhancing NF-κB signalling. These studies show a novel role for Glrx in post-ischaemic neovascularization, which could define a potential target for therapy of impaired angiogenesis in pathological conditions including diabetes.

scholarly journals Islet vascularization is regulated by primary endothelial cilia via VEGF-A-dependent signaling

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yan Xiong ◽  
M Julia Scerbo ◽  
Anett Seelig ◽  
Francesco Volta ◽  
Nils O'Brien ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Primary Cilia ◽  
Capillary Density ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Downstream Signaling ◽  
Vegfr2 Signaling ◽  
And Migration ◽  
Endothelial Growth Factor

Islet vascularization is essential for intact islet function and glucose homeostasis. We have previously shown that primary cilia directly regulate insulin secretion. However, it remains unclear whether they are also implicated in islet vascularization. At eight weeks, murine Bbs4-/-islets show significantly lower intra-islet capillary density with enlarged diameters. Transplanted Bbs4-/- islets exhibit delayed re-vascularization and reduced vascular fenestration after engraftment, partially impairing vascular permeability and glucose delivery to β-cells. We identified primary cilia on endothelial cells as the underlying cause of this regulation, via the vascular endothelial growth factor-A (VEGF-A)/VEGF receptor 2 (VEGFR2) pathway. In vitro silencing of ciliary genes in endothelial cells disrupts VEGF-A/VEGFR2 internalization and downstream signaling. Consequently, key features of angiogenesis including proliferation and migration are attenuated in human BBS4 silenced endothelial cells. We conclude that endothelial cell primary cilia regulate islet vascularization and vascular barrier function via the VEGF-A/VEGFR2 signaling pathway.

scholarly journals Lysophosphatidic Acid Up-Regulates Expression of Interleukin-8 and -6 in Granulosa-Lutein Cells through Its Receptors and Nuclear Factor-κB Dependent Pathways: Implications for Angiogenesis of Corpus Luteum and Ovarian Hyperstimulation Syndrome

2008 ◽  
Vol 93 (3) ◽  
pp. 935-943 ◽  
Author(s):  
Shee-Uan Chen ◽  
Chia-Hung Chou ◽  
Hsinyu Lee ◽  
Chi-Hong Ho ◽  
Chung-Wu Lin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lysophosphatidic Acid ◽  
Ovarian Hyperstimulation Syndrome ◽  
Umbilical Vein ◽  
Nuclear Factor Κb ◽  
Ovarian Hyperstimulation ◽  
Vascular Endothelial ◽  
Nuclear Factor ◽  
Lpa Receptors ◽  
Endothelial Growth Factor

Abstract Context: Lysophosphatidic acid (LPA) was found at significant amounts in follicular fluid of preovulatory follicle. The lysophospholipase D activity of serum from women receiving ovarian stimulation was higher than women with natural cycles. Angiogenic cytokines, including IL-6, IL-8, and vascular endothelial growth factor, increased in plasma and ascites of patients with ovarian hyperstimulation syndrome. The role of LPA in ovarian follicles is unclear. Objective: Our objective was to investigate the expression of LPA receptors and function of LPA in granulosa-lutein cells. Design: Granulosa-lutein cells were obtained from women undergoing in vitro fertilization. We examined the expression of LPA receptors using RT-PCR. The effects of LPA on the expression of IL-6, IL-8, and vascular endothelial growth factor were examined. Signal pathways of LPA were delineated. The functions of secretory angiogenic factors were tested using human umbilical vein endothelial cells. Results: The LPA1, LPA2, and LPA3 receptors’ mRNA was identified in granulosa-lutein cells. LPA enhanced IL-8 and IL-6 expressions in a dose- and time-dependent manner. LPA functioned via LPA receptors, Gi protein, MAPK/ERK, p38, phosphatidylinositol 3-kinase/Akt, and nuclear factor-κB, and transactivation of epidermal growth factor receptor. LPA induced IL-8 and IL-6 through different pathways. LPA-induced IL-8 and IL-6 increased permeability of human umbilical vein endothelial cell monolayer. Conclusions: LPA induces IL-8 and IL-6 expressions through LPA receptors and nuclear factor-κB dependent pathways in granulosa-lutein cells. The LPA in preovulatory follicles may play a role in the angiogenesis of corpus luteum. Large amounts of LPA-induced IL-8 and IL-6 from multiple corpora luteae of stimulated ovaries may be one of the pathophysiological causes of ovarian hyperstimulation syndrome.

Abstract 4572: Reduced Cardiac Progenitors in the Right Ventricle of Cyanotic Heart Lesions: Insights into RV Adaptation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Naila Mahmut ◽  
Caroline Kinnear ◽  
Megan Thompson ◽  
Patrick Shannon ◽  
David Chitayat ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Later Life ◽  
Capillary Density ◽  
Vascular Endothelial ◽  
Cardiac Progenitors ◽  
The Right ◽  
Von Willebrand ◽  
Endothelial Growth Factor ◽  
Left Heart Syndrome ◽  
Heart Lesions

The RV in hypoplastic left heart syndrome (HLHS) and Tetralogy of Fallot (TOF) is exposed to hypoxia and abnormal load which may lead to RV dysfunction despite surgical repair. The ability of hypoxia to upregulate angiogenic signaling in the RV is not known. We measured vascular endothelial growth factor (VEGF) mediated regulation of cardiac progenitors in the RV of patients with HLHS and TOF. Methods: RV myocardial samples were obtained from 6 pts with HLHS (age 0.96±1.5 yrs), 6 pts with TOF (age 3.5±6.3 yrs) and 9 age-matched controls with structurally normal hearts (age 0.16±0.3 yrs) at surgery/transplant/autopsy. The following were measured: VEGF, thymosin β-4 (recruits progenitors), Nkx2.5 (myocyte precursor), Flk-1 (smooth muscle progenitor), CD34 (endothelial progenitor), and von willebrand factor (vWf) (endothelial marker). Results: (i) VEGF and thymosin β-4 expression was lower in HLHS vs controls. This was associated with reduced cardiac progenitors and lower myocardial capillary density vs controls (0.14±0.01 vs 0.55±0.16, p<0.05). (ii) VEGF expression was preserved but thymosin β-4 was reduced in RV in TOF. This was associated with preserved myocyte progenitors but reduction in endothelial and smooth muscle lineages and reduced capillary density vs controls (0.13±0.03 vs 0.55±0.16, p<0.05) (Figure 1 ). Conclusion: Hypoxia fails to induce an angiogenic response in the RV in cyanotic heart lesions. This may be due to reduced VEGF (HLHS) or impaired coupling of VEGF to thymosin β-4 (TOF). This maladaptation may contribute to post-operative RV dysfunction and lower RV regenerative capacity in later life. Figure 1: Reduced capillary density (red) in HLHS and TOF

Delayed Laser photocoagulation following intravitreal anti–vascular endothelial growth factor injection allows immature retinal vessels to regrow without recurrence of retinopathy of prematurity

2019 ◽  
Author(s):  
Ki Yup Nam ◽  
Ji Eun Lee ◽  
Joo Eun Lee ◽  
Hyun Wong Kim ◽  
Sang Joon Lee
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Laser Photocoagulation ◽  
Retinal Vessel ◽  
Disease Recurrence ◽  
Retinal Vessels ◽  
Vascular Endothelial ◽  
Zone Ii ◽  
Vessel Development ◽  
Endothelial Growth Factor

Abstract Purpose: The effects of delayed laser photocoagulation (LP) for ROP patients who received intravitreal anti–vascular endothelial growth factor injections (IVAs) on peripheral vascularization and disease recurrence in ROP patients. Methods: A total of 26 consecutive infant eyes of 14 patients who received IVA treatments were retrospectively investigated. The patients were divided into two groups depending on the initial treatment as follows: IVA group and prompt LP group. Recurrence of ROP, growth of the retinal vessels, and associated complications were evaluated. Results: There were 16 eyes in the IVA group and 10 eyes in the LP group. In the IVA group, delayed LP was performed in six eyes due to recurrences of ROP. In 16 eyes of the IVA group, the retinal vessels grew upto Zone III in eyes received IVA only. Among the IVA groups, Delayed LP was needed in six eyes due to ROP recurrence following IVA. Delayed LP was performed average 7~8 weeks after IVA, which could give the immature neurovascular tissues time to continue vascular development upto Zone II without further ROP recurrence. However, the prompt LP group did not show vessel development beyond the laser scar. Conclusions: Delayed LP following IVA might provide a chance for retinal vessel development in the immature retina to continue without unexpected ROP recurrences.

scholarly journals Upregulation of VEGF-A Without Angiogenesis in a Mouse Model of Dilated Cardiomyopathy Caused by Mitochondrial Dysfunction

2002 ◽  
Vol 50 (7) ◽  
pp. 935-944 ◽  
Author(s):  
Emma Tham ◽  
Jianming Wang ◽  
Fredrik Piehl ◽  
Günther Weber
Keyword(s):  
Transcription Factor ◽  
Dilated Cardiomyopathy ◽  
Capillary Density ◽  
Vascular Endothelial ◽  
Protein Levels ◽  
Mitochondrial Transcription Factor ◽  
Mitochondrial Transcription Factor A ◽  
Respiratory Chain Activity ◽  
Endothelial Growth Factor

Angiogenesis is implicated in a variety of human pathologies and may also play a role in the progression of heart failure. We have studied the expression of members of the vascular endothelial growth factor (VEGF) and the angiopoietin families and their receptors in mice lacking the mitochondrial transcription factor A. These mice lack functional respiratory chain activity in their myocytes and develop dilated cardiomyopathy (DCM) postnatally. We studied the hearts of the knockout mice by in situ hybridization, Western blotting analysis, and immunohistochemistry. VEGF-A mRNA and protein levels were elevated in the myocardium of the knockouts. Levels of the hypoxia inducible transcription factor 1 alpha (HIF1α) and of glyceraldehyde-3-phosphate dehydrogenase transcripts were also increased, whereas those of angiopoietin−1 and −2 were reduced. Despite the striking upregulation of VEGF-A, there was no increase in capillary density in the knockout hearts. This study suggests that a disturbance in angiogenesis may contribute to the pathogenesis of DCM.

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