scholarly journals Suppression of Development of Ankylosing Spondylitis Through Soluble Flt-1

2015 ◽  
Vol 37 (6) ◽  
pp. 2135-2142 ◽  
Author(s):  
Zhongxiang Yu ◽  
Yuting Zhang ◽  
Ningyang Gao ◽  
Kuang Yong
Keyword(s):  
Endothelial Cells ◽  
Ankylosing Spondylitis ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Treatment Results ◽  
Vegf Signaling ◽  
Before And After ◽  
Endothelial Growth Factor ◽  
Pro Inflammatory Cytokines

Background/Aims: Circulating monocytes/macrophages are origins of osteoclasts that mediate the development of ankylosing spondylitis (AS). Moreover, infiltrated macrophages facilitate the AS progression through production and secretion of pro-inflammatory cytokines. Thus, suppression of the recruitment of circulating monocytes/macrophages may be an effective AS treatment, which is, however, not available so far in clinic. Soluble fms-like tyrosine kinase-1 (sFlt-1) is a decoy receptor for vascular endothelial growth factor (VEGF) to compete with VEGF receptor (VEGFR2) for VEGF binding in endothelial cells, while its application in treating AS and effects on the recruitment of circulating monocytes/macrophages has not been reported before. Methods: We used a proteoglycan-induced arthritis (PGIA) mouse model for human AS. We injected sFlt-1 into the articular cavity and evaluated its effects on PGIA by incidence of arthritis, and clinical and pathological arthritis severity. We isolated and analyzed macrophages and endothelial cells in the articular cavity before and after treatment. Results: Injection of sFlt-1 significantly decreased the incidence and severity of PGIA in mice, and significantly reduced the number of infiltrated macrophages, possibly through reduction of vessel permeability, in a VEGFR2-dependent manner. Conclusion: Our data suggest that sFlt-1 may have a therapeutic effect on AS, resulting from suppression of VEGF signaling-mediated recruitment of circulating monocytes/macrophages.

Characterization of the vasculogenic block in the absence of vascular endothelial growth factor-A

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 1979-1987 ◽  
Author(s):  
Victoria L. Bautch ◽  
Sambra D. Redick ◽  
Aaron Scalia ◽  
Marco Harmaty ◽  
Peter Carmeliet ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Embryonic Stem ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Vegf Signaling ◽  
Homozygous Mutant ◽  
Endothelial Growth Factor ◽  
Rna Levels

Abstract Vascular endothelial growth factor (VEGF) signaling is required for both differentiation and proliferation of vascular endothelium. Analysis of differentiated embryonic stem cells with one or both VEGF-A alleles deleted showed that both the differentiation and the expansion of endothelial cells are blocked during vasculogenesis. Blood island formation was reduced by half in hemizygous mutant VEGF cultures and by 10-fold in homozygous mutant VEGF cultures. Homozygous mutant cultures could be partially rescued by the addition of exogenous VEGF. RNA levels for the endothelial adhesion receptors ICAM-2 and PECAM were reduced in homozygous mutant cultures, but ICAM-2 RNA levels decreased substantially, whereas PECAM RNA levels remained at hemizygous levels. The quantitative data correlated with the antibody staining patterns because cells that were not organized into vessels expressed PECAM but not ICAM-2. These PECAM+ cell clumps accumulated in mutant cultures as vessel density decreased, suggesting that they were endothelial cell precursors blocked from maturation. A subset of PECAM+ cells in clumps expressed stage-specific embryonic antigen-1 (SSEA-1), and all were ICAM-2(−) and CD34(−), whereas vascular endothelial cells incorporated into vessels were PECAM(+), ICAM-2(+), CD34(+), and SSEA-1(−). Analysis of flk-1 expression indicated that a subset of vascular precursor cells coexpressed PECAM and flk-1. These data suggest that VEGF signaling acts in a dose-dependent manner to affect both a specific differentiation step and the subsequent expansion of endothelial cells.

scholarly journals Regulation of the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR by estradiol through VEGF in uterus

2006 ◽  
Vol 188 (1) ◽  
pp. 91-99 ◽  
Author(s):  
M A J Hervé ◽  
G Meduri ◽  
F G Petit ◽  
T S Domet ◽  
G Lazennec ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Receptor Expression ◽  
Maximal Response ◽  
Target Cells ◽  
Vegf Receptor ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

The induction of vascular endothelial growth factor (VEGF) expression by 17β-estradiol (E2) in many target cells, including epithelial cells, fibroblasts and smooth muscle cells, suggests a role for this hormone in the modulation of angiogenesis and vascular permeability. We have already described a cyclic increase in Flk-1/KDR-expressing capillaries in the human endometrium during the proliferative and mid-secretory phases, strongly suggestive of an E2 effect on Flk-1/KDR expression in the endometrial capillaries. However, it is unclear whether these processes are due to a direct effect of E2 on endothelial cells. Using immunohistochemistry, we report an increase in Flk-1/KDR expression in endometrial capillaries of ovariectomized mice treated with E2, or both E2 and progesterone. This process is mediated through estrogen receptor (ER) activation. In vitro experiments using quantitative RT-PCR analysis demonstrate that Flk-1/KDR expression was not regulated by E2 in human endothelial cells from the microcirculation (HMEC-1) or macrocirculation (HUVEC), even in endothelial cells overexpressing ERα or ERβ after ER-mediated adenovirus infection. In contrast, Flk-1/KDR expression was up-regulated by VEGF itself, in a time- and dose-dependent manner, with the maximal response at 10 ng/ml. Thus, we suggest that E2 up-regulates Flk-1/KDR expression in vivo in endothelial cells mainly through the modulation of VEGF by a paracrine mechanism. It is currently unknown whether or not the endothelial origin might account for differences in the E2-modulation of VEGF receptor expression, particularly in relation to the vascular bed of sex steroid-responsive tissues.

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 Lipid Raft Association Stabilizes VEGF Receptor 2 in Endothelial Cells

2021 ◽  
Vol 22 (2) ◽  
pp. 798
Author(s):  
Ibukunoluwapo O. Zabroski ◽  
Matthew A. Nugent
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Lipid Rafts ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Potential Mechanism ◽  
Lysosomal Degradation ◽  
Extracellular Signal ◽  
The Stability ◽  
Endothelial Growth Factor

The binding of vascular endothelial growth factor A (VEGF) to VEGF receptor-2 (VEGFR-2) stimulates angiogenic signaling. Lipid rafts are cholesterol-dense regions of the plasma membrane that serve as an organizational platform for biomolecules. Although VEGFR2 has been shown to colocalize with lipid rafts to regulate its activation, the effect of lipid rafts on non-activated VEGFR2 has not been explored. Here, we characterized the involvement of lipid rafts in modulating the stability of non-activated VEGFR2 in endothelial cells using raft disrupting agents: methyl-β-cyclodextrin, sphingomyelinase and simvastatin. Disrupting lipid rafts selectively decreased the levels of non-activated VEGFR2 as a result of increased lysosomal degradation. The decreased expression of VEGFR2 translated to reduced VEGF-activation of the extracellular signal-regulated protein kinases (ERK). Overall, our results indicate that lipid rafts stabilize VEGFR2 and its associated signal transduction activities required for angiogenesis. Thus, modulation of lipid rafts may provide a means to regulate the sensitivity of endothelial cells to VEGF stimulation. Indeed, the ability of simvastatin to down regulate VEGFR2 and inhibit VEGF activity suggest a potential mechanism underlying the observation that this drug improves outcomes in the treatment of certain cancers.

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 Convergence of VEGF and YAP/TAZ signaling: Implications for angiogenesis and cancer biology

2018 ◽  
Vol 11 (552) ◽  
pp. eaau1165 ◽  
Author(s):  
Ameer L. Elaimy ◽  
Arthur M. Mercurio
Keyword(s):  
Endothelial Cells ◽  
Tumor Cells ◽  
Cancer Biology ◽  
Vascular Endothelial ◽  
Vascular Growth ◽  
Vegf Signaling ◽  
Pathological Angiogenesis ◽  
Cytoskeletal Dynamics ◽  
Rho Family ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) stimulates endothelial cells to promote both developmental and pathological angiogenesis. VEGF also directly affects tumor cells and is associated with the initiation, progression, and recurrence of tumors, as well as the emergence and maintenance of cancer stem cells (CSCs). Studies have uncovered the importance of the transcriptional regulators YAP and TAZ in mediating VEGF signaling. For example, VEGF stimulates the GTPase activity of Rho family members and thereby alters cytoskeletal dynamics, which contributes to the activation of YAP and TAZ. In turn, YAP- and TAZ-mediated changes in gene expression sustain Rho family member activity and cytoskeletal effects to promote both vascular growth and remodeling in endothelial cells and the acquisition of stem-like traits in tumor cells. In this Review, we discuss how these findings further explain the pathophysiological roles of VEGF and YAP/TAZ, identify their connections to other receptor-mediated pathways, and reveal ways of therapeutically targeting their convergent signals in patients.

scholarly journals An unexpected tail of VEGF and PlGF in pre-eclampsia

2011 ◽  
Vol 39 (6) ◽  
pp. 1576-1582 ◽  
Author(s):  
David O. Bates
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Endothelial Activation ◽  
Placental Growth Factor ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Physiological Changes ◽  
Vegf Family Members ◽  
Endothelial Growth Factor ◽  
Vegf Isoforms

PET (pre-eclamptic toxaemia), characterized by pregnancy-related hypertension and proteinuria, due to widespread endothelial dysfunction, is a primary cause of maternal morbidity. Altered circulating factors, particularly the VEGF (vascular endothelial growth factor) family of proteins and their receptors, are thought to be key contributors to this disease. Plasma from patients with PET induces numerous cellular and physiological changes in endothelial cells, indicating the presence of a circulating imbalance of the normal plasma constituents. These have been narrowed down to macromolecules of the VEGF family of proteins and receptors. It has been shown that responses of endothelial cells in intact vessels to plasma from patients with pre-eclampsia is VEGF-dependent. It has recently been shown that this may be specific to the VEGF165b isoform, and blocked by addition of recombinant human PlGF (placental growth factor). Taken together with results that show that sVEGFR1 (soluble VEGF receptor 1) levels are insufficient to bind VEGF-A in human plasma from patients with pre-eclampsia, and that other circulating macromolecules bind, but do not inactivate, VEGF-A, this suggests that novel hypotheses involving altered bioavailability of VEGF isoforms resulting from reduced or bound PlGF, or increased sVEGFR1 increasing biological activity of circulating plasma, could be tested. This suggests that knowing how to alter the balance of VEGF family members could prevent endothelial activation, and potentially some symptoms, of pre-eclampsia.

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