scholarly journals The biological responses and mechanisms of endothelial cells to magnesium alloy

2021 ◽  
Vol 8 (3) ◽  
Author(s):  
Zhe Hou ◽  
Maolong Xiang ◽  
Nuoya Chen ◽  
Xiao Cai ◽  
Bo Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Magnesium Alloy ◽  
Global Gene Expression ◽  
Mg Alloy ◽  
Great Promise ◽  
Biological Responses ◽  
Global Gene Expression Profiling ◽  
Good Biocompatibility ◽  
And Migration

Abstract Due to its good biocompatibility and degradability, magnesium alloy (Mg alloy) has shown great promise in cardiovascular stent applications. Rapid stent re-endothelialization is derived from migrated and adhered endothelial cells (ECs), which is an effective way to reduce late thrombosis and inhibit hyperplasia. However, fundamental questions regarding Mg alloy affecting migration and adhesion of ECs are not fully understood. Here, we evaluated the effects of Mg alloy on the ECs proliferation, adhesion and migration. A global gene expression profiling of ECs co-culturing with Mg alloy was conducted, and the adhesion- and migration-related genes were examined. We found that Mg alloy had no adverse effects on ECs viability but significantly affected ECs migration and adhesion. Co-cultured with Mg alloy extract, ECs showed contractive adhesion morphology and decreased motility, which was supported by the down-regulation of adhesion-related genes (Paxillin and Vinculin) and migration-related genes (RAC 1, Rho A and CDC 42). Accordingly, the re-endothelialization of Mg alloy stent was inhibited in vivo. Our results may provide new inspiration for improving the broad application of Mg alloy stents.

scholarly journals Hedgehog Signaling Inhibition by Smoothened Antagonist BMS-833923 Reduces Osteoblast Differentiation and Ectopic Bone Formation of Human Skeletal (Mesenchymal) Stem Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Nihal AlMuraikhi ◽  
Nuha Almasoud ◽  
Sarah Binhamdan ◽  
Ghaydaa Younis ◽  
Dalia Ali ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Formation ◽  
Osteoblast Differentiation ◽  
Global Gene Expression ◽  
Ectopic Bone Formation ◽  
Ectopic Bone ◽  
In Vitro Mineralization ◽  
Global Gene Expression Profiling

Background. Hedgehog (Hh) signaling is essential for osteoblast differentiation of mesenchymal progenitors during endochondral bone formation. However, the critical role of Hh signaling during adult bone remodeling remains to be elucidated. Methods. A Smoothened (SMO) antagonist/Hedgehog inhibitor, BMS-833923, identified during a functional screening of a stem cell signaling small molecule library, was investigated for its effects on the osteoblast differentiation of human skeletal (mesenchymal) stem cells (hMSC). Alkaline phosphatase (ALP) activity and Alizarin red staining were employed as markers for osteoblast differentiation and in vitro mineralization capacity, respectively. Global gene expression profiling was performed using the Agilent® microarray platform. Effects on in vivo ectopic bone formation were assessed by implanting hMSC mixed with hydroxyapatite-tricalcium phosphate granules subcutaneously in 8-week-old female nude mice, and the amount of bone formed was assessed using quantitative histology. Results. BMS-833923, a SMO antagonist/Hedgehog inhibitor, exhibited significant inhibitory effects on osteoblast differentiation of hMSCs reflected by decreased ALP activity, in vitro mineralization, and downregulation of osteoblast-related gene expression. Similarly, we observed decreased in vivo ectopic bone formation. Global gene expression profiling of BMS-833923-treated compared to vehicle-treated control cells, identified 348 upregulated and 540 downregulated genes with significant effects on multiple signaling pathways, including GPCR, endochondral ossification, RANK-RANKL, insulin, TNF alpha, IL6, and inflammatory response. Further bioinformatic analysis employing Ingenuity Pathway Analysis revealed significant enrichment in BMS-833923-treated cells for a number of functional categories and networks involved in connective and skeletal tissue development and disorders, e.g., NFκB and STAT signaling. Conclusions. We identified SMO/Hedgehog antagonist (BMS-833923) as a powerful inhibitor of osteoblastic differentiation of hMSC that may be useful as a therapeutic option for treating conditions associated with high heterotopic bone formation and mineralization.

scholarly journals Impaired angiogenesis and altered Notch signaling in mice overexpressing endothelial Egfl7

Blood ◽  
2010 ◽  
Vol 116 (26) ◽  
pp. 6133-6143 ◽  
Author(s):  
Donna Nichol ◽  
Carrie Shawber ◽  
Michael J. Fitch ◽  
Kathryn Bambino ◽  
Anshula Sharma ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Notch Signaling ◽  
Target Genes ◽  
Critical Role ◽  
Endothelial Cell Proliferation ◽  
Vascular Patterning ◽  
Cardiac Morphogenesis ◽  
Epidermal Growth ◽  
And Migration

Abstract Epidermal growth factor-like domain 7 (Egfl7) is important for regulating tubulogenesis in zebrafish, but its role in mammals remains unresolved. We show here that endothelial overexpression of Egfl7 in transgenic mice leads to partial lethality, hemorrhaging, and altered cardiac morphogenesis. These defects are accompanied by abnormal vascular patterning and remodeling in both the embryonic and postnatal vasculature. Egfl7 overexpression in the neonatal retina results in a hyperangiogenic response, and EGFL7 knockdown in human primary endothelial cells suppresses endothelial cell proliferation, sprouting, and migration. These phenotypes are reminiscent of Notch inhibition. In addition, our results show that EGFL7 and endothelial-specific NOTCH physically interact in vivo and strongly suggest that Egfl7 antagonizes Notch in both the postnatal retina and in primary endothelial cells. Specifically, Egfl7 inhibits Notch reporter activity and down-regulates the level of Notch target genes when overexpressed. In conclusion, we have uncovered a critical role for Egfl7 in vascular development and have shown that some of these functions are mediated through modulation of Notch signaling.

Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1243-1250 ◽  
Author(s):  
Benoit Favier ◽  
Antoine Alam ◽  
Pauline Barron ◽  
Jacques Bonnin ◽  
Patricia Laboudie ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Survival ◽  
Endothelial Cell Migration ◽  
Human Endothelial Cell ◽  
Human Endothelial Cells ◽  
Endothelial Cell Survival ◽  
Biological Responses ◽  
And Migration ◽  
Endothelial Growth Factor

Abstract Neuropilin 2 (NRP2) is a receptor for the vascular endothelial growth factor (VEGF) and the semaphorin (SEMA) families, 2 unrelated ligand families involved in angiogenesis and neuronal guidance. NRP2 specifically binds VEGF-A and VEGF-C, although the biological relevance of these interactions in human endothelial cells is poorly understood. In this study, we show that both VEGF-A and VEGF-C induce the interaction of NRP2 with VEGFR-2. This interaction correlated with an enhancement of the VEGFR-2 phosphorylation threshold. Overexpression of NRP2 in primary human endothelial cells promoted cell survival induced by VEGF-A and VEGF-C. In contrast, SEMA3F, another ligand for NRP2, was able to inhibit human endothelial cell survival and migration induced by VEGF-A and VEGF-C. Moreover, a siRNA targeting specifically NRP2 was a potent inhibitor of human endothelial cell migration induced by VEGF-A and VEGF-C. Thus, our data indicate that NRP2 acts as a coreceptor that enhances human endothelial cell biological responses induced by VEGF-A and VEGF-C.

scholarly journals Multivalent conjugates of basic fibroblast growth factor enhance in vitro proliferation and migration of endothelial cells

2018 ◽  
Vol 6 (5) ◽  
pp. 1076-1083 ◽  
Author(s):  
Aline Zbinden ◽  
Shane Browne ◽  
Eda I. Altiok ◽  
Felicia L. Svedlund ◽  
Wesley M. Jackson ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Great Promise ◽  
Fibroblast Growth ◽  
In Vitro Proliferation ◽  
And Migration ◽  
Regenerative Therapies ◽  
Proliferation And Migration

Multivalent growth factor conjugates hold great promise for regenerative therapies.

Tumour growth inhibition and anti-angiogenic effects using curcumin correspond to combined PDE2 and PDE4 inhibition

2015 ◽  
Vol 113 (02) ◽  
pp. 319-328 ◽  
Author(s):  
Abdurazzag Abusnina ◽  
Thérèse Keravis ◽  
Qingwei Zhou ◽  
Hélène Justiniano ◽  
Annelise Lobstein ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumour Growth ◽  
Umbilical Vein ◽  
Camp Level ◽  
Pde4 Inhibitor ◽  
Endothelial Cell Proliferation ◽  
And Migration ◽  
Proliferation And Migration

SummaryVascular endothelial growth factor (VEGF) plays a major role in angiogenesis by stimulating endothelial cells. Increase in cyclic AMP (cAMP) level inhibits VEGF-induced endothelial cell proliferation and migration. Cyclic nucleotide phosphodiesterases (PDEs), which specifically hydrolyse cyclic nucleotides, are critical in the regulation of this signal transduction. We have previously reported that PDE2 and PDE4 up-regulations in human umbilical vein endothelial cells (HUVECs) are implicated in VEGF-induced angiogenesis and that inhibition of PDE2 and PDE4 activities prevents the development of the in vitro angiogenesis by increasing cAMP level, as well as the in vivo chicken embryo angiogenesis. We have also shown that polyphenols are able to inhibit PDEs. The curcumin having anti-cancer properties, the present study investigated whether PDE2 and PDE4 inhibitors and curcumin could have similar in vivo anti-tumour properties and whether the anti-angiogenic effects of curcumin are mediated by PDEs. Both PDE2/PDE4 inhibitor association and curcumin significantly inhibited in vivo tumour growth in C57BL/6N mice. In vitro, curcumin inhibited basal and VEGF-stimulated HUVEC proliferation and migration and delayed cell cycle progression at G0/G1, similarly to the combination of selective PDE2 and PDE4 inhibitors. cAMP levels in HUVECs were significantly increased by curcumin, similarly to rolipram (PDE4 inhibitor) and BAY-60–550 (PDE2 inhibitor) association, indicating cAMP-PDE inhibitions. Moreover, curcumin was able to inhibit VEGF-induced cAMP-PDE activity without acting on cGMP-PDE activity and to modulate PDE2 and PDE4 expressions in HUVECs. The present results suggest that curcumin exerts its in vitro anti-angiogenic and in vivo antitumour properties through combined PDE2 and PDE4 inhibition.

scholarly journals Disrupted PGR-B and ESR1 signaling underlies preconceptional defective decidualization linked to severe preeclampsia

2021 ◽  
Author(s):  
Tamara Garrido-Gomez ◽  
Nerea Castillo-Marco ◽  
Monica Clemente-Ciscar ◽  
Teresa Cordero ◽  
Irene Munoz-Blat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dynamic Network ◽  
Global Gene Expression ◽  
Severe Preeclampsia ◽  
Maternal Adaptation ◽  
Uterine Mucosa ◽  
Transcriptomic Signature ◽  
Global Gene Expression Profiling ◽  
Progesterone Receptor B

Decidualization of the uterine mucosa drives the maternal adaptation to invasion by the placenta. Appropriate depth of placental invasion is needed to support a healthy pregnancy; shallow invasion is associated with the development of severe preeclampsia (sPE). Maternal contribution to sPE through failed decidualization is an important determinant of placental phenotype. However, the molecular mechanism underlaying the in vivo defect linking decidualization to sPE is unknown. Here, we discover the footprint encoding this decidualization defect comprising of 166 genes using global gene expression profiling in decidua from women who developed sPE in a previous pregnancy. This signature allowed us to effectively segregate samples into sPE and control groups. Estrogen receptor 1 (ESR1) and progesterone receptor B (PGR-B) were found highly interconnected with the dynamic network of defective decidualization fingerprint. ESR1 and PGR-B gene expression and protein abundance were remarkably disrupted in sPE. Thus, the transcriptomic signature of impaired decidualization implicates dysregulated hormonal signaling in the decidual endometria in women who developed sPE. These findings reveal a potential footprint that may be leverage for a preconception or early prenatal screening of sPE risk, thus improving prevention and early treatments.

scholarly journals Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Tamara Garrido-Gomez ◽  
Nerea Castillo-Marco ◽  
Mónica Clemente-Ciscar ◽  
Teresa Cordero ◽  
Irene Muñoz-Blat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dynamic Network ◽  
Interaction Network ◽  
Global Gene Expression ◽  
Severe Preeclampsia ◽  
Protein Abundance ◽  
Previous Pregnancy ◽  
Global Gene Expression Profiling ◽  
Phd Program

Background:Decidualization of the uterine mucosa drives the maternal adaptation to invasion by the placenta. Appropriate depth of placental invasion is needed to support a healthy pregnancy; shallow invasion is associated with the development of severe preeclampsia (sPE). Maternal contribution to sPE through failed decidualization is an important determinant of placental phenotype. However, the molecular mechanism underlying the in vivo defect linking decidualization to sPE is unknown.Methods:Global RNA sequencing was applied to obtain the transcriptomic profile of endometrial biopsies collected from nonpregnant women who suffer sPE in a previous pregnancy and women who did not develop this condition. Samples were randomized in two cohorts, the training and the test set, to identify the fingerprinting encoding defective decidualization in sPE and its subsequent validation. Gene Ontology enrichment and an interaction network were performed to deepen in pathways impaired by genetic dysregulation in sPE. Finally, the main modulators of decidualization, estrogen receptor 1 (ESR1) and progesterone receptor B (PGR-B), were assessed at the level of gene expression and protein abundance.Results:Here, we discover the footprint encoding this decidualization defect comprising 120 genes—using global gene expression profiling in decidua from women who developed sPE in a previous pregnancy. This signature allowed us to effectively segregate samples into sPE and control groups. ESR1 and PGR were highly interconnected with the dynamic network of the defective decidualization fingerprint. ESR1 and PGR-B gene expression and protein abundance were remarkably disrupted in sPE.Conclusions:Thus, the transcriptomic signature of impaired decidualization implicates dysregulated hormonal signaling in the decidual endometria in women who developed sPE. These findings reveal a potential footprint that could be leveraged for a preconception or early prenatal screening of sPE risk, thus improving prevention and early treatments.Funding:This work has been supported by the grant PI19/01659 (MCIU/AEI/FEDER, UE) from the Spanish Carlos III Institute awarded to TGG. NCM was supported by the PhD program FDGENT/2019/008 from the Spanish Generalitat Valenciana. IMB was supported by the PhD program PRE2019-090770 and funding was provided by the grant RTI2018-094946-B-100 (MCIU/AEI/FEDER, UE) from the Spanish Ministry of Science and Innovation with CS as principal investigator. This research was funded partially by Igenomix S.L.

Rapid In Vivo Assessment of the Nano/Bio Interface

2013 ◽  
Author(s):  
Robert L. Tanguay ◽  
Lisa Truong ◽  
Tatiana Zaikova ◽  
James E. Hutchison
Keyword(s):  
Large Scale ◽  
Life Stage ◽  
Significant Risk ◽  
Great Promise ◽  
Life Stages ◽  
Molecular Signaling ◽  
Biological Responses ◽  
Biological Compatibility ◽  
Early Developmental

Recent advances in nanoscience offer great promise for the nanomedicine sector. These advances in the nanotechnology field will undoubtedly increase both human and environmental exposures to engineered nanomaterials. Whether these exposures pose a significant risk remains uncertain. Despite recent collective progress there remain gaps in our understanding of the nanomaterials physiochemical properties that drive or dictate biological compatibility. The development and implementation of rapid relevant and efficient testing strategies to assess these emerging materials prior to large-scale exposures could help advance this exciting field. I will present a powerful approach that utilizes a dynamic in vivo zebrafish embryonic assay to rapidly define the biological responses to nanomaterial exposures. Early developmental life stages are often uniquely sensitive to environmental insults, due in part to the enormous changes in cellular differentiation, proliferation and migration required to form the required cell types, tissues and organs. Molecular signaling underlies all of these processes. Most toxic responses result from disruption of proper molecular signaling, thus, early developmental life stages are perhaps the ideal life stage to determine if nanomaterials perturb normal biological pathways. Through automation and rapid throughput approaches, a systematic and iterative strategy has been deployed to help elucidate the nanomaterials properties that drive biological responses.

Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells

2005 ◽  
Vol 289 (2) ◽  
pp. L196-L206 ◽  
Author(s):  
Bing Zhu ◽  
Samuel Strada ◽  
Troy Stevens
Keyword(s):  
Endothelial Cells ◽  
Cell Growth ◽  
Dominant Role ◽  
Pde5 Inhibitor ◽  
Hydrolytic Activity ◽  
Pulmonary Endothelium ◽  
Intracellular Cgmp ◽  
Inhibit Cell Growth ◽  
And Migration

Sustained increases in intracellular cGMP concentrations ([cGMP]i) inhibit cell growth and induce apoptosis. We now report that a cGMP-specific phosphodiesterase, PDE5, plays a dominant role in regulating [cGMP]i transitions that inhibit cell growth and control susceptibility to apoptosis in pulmonary endothelium. Atrial natriuretic peptide (ANP) activates guanylyl cyclase A/B and induces a rapid [cGMP]i rise 2–5 min after its application, in both pulmonary arterial endothelial cells (PAECs) and pulmonary microvascular endothelial cells (PMVECs). However, increased [cGMP]i in PAECs is transient and decays within 10 min due to cytosolic PDE5 hydrolytic activity. Increased [cGMP]i in PMVECs is sustained for >3 h due to the absence of PDE5. Indeed, at any ANP concentration, the sustained (30 min) [cGMP]i rise is greater in PMVECs than in PAECs, unless PAECs are also treated with the PDE5 inhibitor zaprinast. Using RT-PCR, Western blot analysis, immunoprecipitation, and DEAE chromatography, we resolved the expression and activity of PDE 5A1/A2 only in PAECs. Similarly, PDE5 expression was restricted to extra-alveolar endothelium in vivo. ANP induced growth inhibition and apoptosis in PMVECs, but similar effects were not seen in PAECs unless ANP treatment was combined with zaprinast. ANP blocked the VEGF-induced proliferation and migration in PMVECs. Collectively, these data suggest that PDE5-regulated [cGMP]i controls endothelial cell growth and apoptosis, representing a mechanism of heterogeneity between two endothelial phenotypes.

Abstract 12659: Hepatoma-Derived Growth Factor Related Protein-3 as a Novel Endothelial Ligand

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Michelle LeBlanc ◽  
Weiwen Wang ◽  
Feiye Guo ◽  
Chen Shen ◽  
Rui Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Growth Effect ◽  
Human Aorta ◽  
Related Protein ◽  
And Migration ◽  
Endothelial Ligands

Background: Endothelial ligands extrinsically regulate a broad spectrum of vascular functions with therapeutic potentials, but are traditionally identified on a case-by-case basis with technical challenges. We recently developed open reading frame phage display (OPD) for unbiased identification of phagocytosis ligands. In this study, we identified hepatoma-derived growth factor related protein-3 (HRP-3) as a putative endothelial ligand by OPD. We hypothesized that HRP-3 is a novel endothelial growth factor, capable of promoting endothelial cell (EC) growth and migration. Methods and Results: We performed 3 rounds of in vivo phage binding selection in mice with an OPD library, screened enriched phage clones by next generation DNA sequencing, and identified HRP-3 as one of the putative endothelial ligands. To confirm the finding, clonal phages displaying HRP-3, VEGF and GFP were generated and analyzed for their binding to human umbilical vein endothelial cells (HUVECs). The results show that HRP-3-Phage and VEGF-Phage had significantly higher binding to HUVECs than GFP-Phage. Functional analysis showed that purified recombinant HRP-3 significantly increased the proliferation of HUVECs at 24 and 48 h, whereas VEGF induced significant growth only at 48 h. Consistent with these findings, HRP-3 significantly stimulated cell proliferation by MTT assay. In vitro wound-healing assay indicated that both HRP-3 (500 ng/ml) and VEGF (50 ng/ml) significantly promoted the migration of HUVECs into the denuded area. To dissect the downstream signaling pathway, we demonstrated that HRP-3 significantly induced ERK1/2 phosphorylation in HUVECs after 10 min treatment. Similar effects of HRP-3 and VEGF on EC growth, migration, and ERK activation were also verified using human aorta endothelial cells. Conclusions: Our findings demonstrate that HRP-3 is a novel ligand, capable of promoting proliferation and migration of ECs. The pro-growth effect of HRP-3 is at least partially mediated through ERK pathway activation. These results in turn support the broad applicability of OPD for the systematic discovery of endothelial ligands.

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