scholarly journals The blood flow-klf6a-tagln2 axis drives vessel pruning in zebrafish by regulating endothelial cell rearrangement and actin cytoskeleton dynamics

PLoS Genetics ◽  
2021 ◽  
Vol 17 (7) ◽  
pp. e1009690
Author(s):  
Lin Wen ◽  
Tao Zhang ◽  
Jinxuan Wang ◽  
Xuepu Jin ◽  
Muhammad Abdul Rouf ◽  
...  
Keyword(s):  
Blood Flow ◽  
Endothelial Cell ◽  
Actin Cytoskeleton ◽  
Critical Role ◽  
Large Diameter ◽  
Zebrafish Embryos ◽  
Downstream Target ◽  
Cytoskeleton Remodeling ◽  
Transgenic Embryos ◽  
Cytoskeleton Dynamics

Recent studies have focused on capillary pruning in various organs and species. However, the way in which large-diameter vessels are pruned remains unclear. Here we show that pruning of the zebrafish caudal vein (CV) from ventral capillaries of the CV plexus in different transgenic embryos is driven by endothelial cell (EC) rearrangement, which involves EC nucleus migration, junction remodeling, and actin cytoskeleton remodeling. Further observation reveals a growing difference in blood flow velocity between the two vessels in CV pruning in zebrafish embryos. With this model, we identify the critical role of Kruppel-like factor 6a (klf6a) in CV pruning. Disruption of klf6a functioning impairs CV pruning in zebrafish. klf6a is required for EC nucleus migration, junction remodeling, and actin cytoskeleton dynamics in zebrafish embryos. Moreover, actin-related protein transgelin 2 (tagln2) is a direct downstream target of klf6a in CV pruning in zebrafish embryos. Together these results demonstrate that the klf6a-tagln2 axis regulates CV pruning by promoting EC rearrangement.

scholarly journals Adenosine A1 Receptors Promote Vasa Vasorum Endothelial Cell Barrier Integrity via Gi and Akt-Dependent Actin Cytoskeleton Remodeling

PLoS ONE ◽  
2013 ◽  
Vol 8 (4) ◽  
pp. e59733 ◽  
Author(s):  
Nagavedi Siddaramappa Umapathy ◽  
Elzbieta Kaczmarek ◽  
Nooreen Fatteh ◽  
Nana Burns ◽  
Rudolf Lucas ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Actin Cytoskeleton ◽  
Vasa Vasorum ◽  
Adenosine A1 Receptors ◽  
Barrier Integrity ◽  
Adenosine A1 ◽  
Cytoskeleton Remodeling

scholarly journals JNK and PI3K differentially regulate MMP-2 and MT1-MMP mRNA and protein in response to actin cytoskeleton reorganization in endothelial cells

2006 ◽  
Vol 291 (4) ◽  
pp. C579-C588 ◽  
Author(s):  
Eric Ispanovic ◽  
Tara L. Haas
Keyword(s):  
Endothelial Cells ◽  
Matrix Metalloproteinase ◽  
Actin Cytoskeleton ◽  
Mrna Expression ◽  
Protein Production ◽  
Critical Role ◽  
Cytochalasin D ◽  
Matrix Metalloproteinase 2 ◽  
Downstream Target ◽  
Protein Levels

Increased production and activation of matrix metalloproteinase-2 (MMP-2) are critical events in skeletal muscle angiogenesis and are known to occur in response to mechanical stresses. We hypothesized that reorganization of the actin cytoskeleton would increase endothelial cell production and activation of MMP-2 and that this increase would require a MAPK-dependent signaling pathway in endothelial cells. The pharmacological actin depolymerization agent cytochalasin D increased expression of MMP-2 and membrane type 1-matrix metalloproteinase (MT1-MMP) mRNA, and this was reduced significantly in the presence of the JNK inhibitor SP600125. Activation of JNK by anisomycin was sufficient to induce expression of both MMP-2 and MT1-MMP mRNA in quiescent cells. Downregulation of c-Jun, a downstream target of JNK, with small interference (si)RNA inhibited MMP-2 expression in response to anisomycin. Inhibition of phosphoinositide 3-kinase (PI3K), but not JNK, significantly decreased the amount of active MMP-2 following cytochalasin D stimulation with a concurrent decrease in MT1-MMP protein. Physiological reorganization of actin occurs during VEGF stimulation. VEGF-induced MMP-2 protein production and activation, as well as MT1-MMP protein production, depended on PI3K activity. VEGF-induced MMP-2 mRNA expression was reduced by inhibition of JNK or by treatment with c-Jun siRNA. In summary, our results provide novel insight into the signaling cascades initiated in the early stages of angiogenesis through the reorganization of the actin cytoskeleton and demonstrate a critical role for JNK in regulating MMP-2 and MT1-MMP mRNA expression, whereas PI3K regulates protein levels of both MMP-2 and MT1-MMP.

LIMK2-1, a new isoform of human LIMK2, regulates actin cytoskeleton remodeling via a different signaling pathway than that of its two homologs, LIMK2a and LIMK2b

2018 ◽  
Vol 475 (23) ◽  
pp. 3745-3761 ◽  
Author(s):  
Béatrice Vallée ◽  
Hélène Cuberos ◽  
Michel Doudeau ◽  
Fabienne Godin ◽  
David Gosset ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Neurological Diseases ◽  
Mrna Level ◽  
Fiber Formation ◽  
Actin Stress Fiber ◽  
C Terminus ◽  
Targeted Treatments ◽  
Cytoskeleton Remodeling ◽  
Inhibitory Domain ◽  
Cytoskeleton Dynamics

LIMK1 and LIMK2 (LIMKs, LIM kinases) are kinases that play a crucial role in cytoskeleton dynamics by independently regulating both actin filament and microtubule remodeling. LIMK1 and, more recently, LIMK2 have been shown to be involved in cancer development and metastasis, resistance of cancer cells to microtubule-targeted treatments, neurological diseases, and viral infection. LIMKs have thus recently emerged as new therapeutic targets. Databanks describe three isoforms of human LIMK2: LIMK2a, LIMK2b, and LIMK2-1. Evidence suggests that they may not have completely overlapping functions. We biochemically characterized the three isoforms to better delineate their potential roles, focusing on LIMK2-1, which has only been described at the mRNA level in a single study. LIMK2-1 has a protein phosphatase 1 (PP1) inhibitory domain at its C-terminus which its two counterparts do not. We showed that the LIMK2-1 protein is indeed synthesized. LIMK2-1 does not phosphorylate cofilin, the canonical substrate of LIMKs, although it has kinase activity and promotes actin stress fiber formation. Instead, it interacts with PP1 and partially inhibits its activity towards cofilin. Our data suggest that LIMK2-1 regulates actin cytoskeleton dynamics by preventing PP1-mediated cofilin dephosphorylation, rather than by directly phosphorylating cofilin as its two counterparts, LIMK2a and LIMK2b. This specificity may allow for tight regulation of the phospho-cofilin pool, determining the fate of the cell.

scholarly journals Defective flow-migration coupling causes arteriovenous malformations in hereditary hemorrhagic telangiectasia

2021 ◽  
Author(s):  
Hyojin Park ◽  
Jessica Furtado ◽  
Mathilde Poulet ◽  
Minhwan Chung ◽  
Sanguk Yun ◽  
...  
Keyword(s):  
Blood Flow ◽  
Endothelial Cell ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Nuclear Translocation ◽  
Vascular Malformations ◽  
Critical Role ◽  
Cell Polarization ◽  
Endothelial Cell Migration ◽  
Cardiovascular Development

Background: Activin receptor-like kinase 1 (ACVRL1, hereafter ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasia (HHT), a devastating disorder that leads to arteriovenous malformations (AVMs). Here we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles. Methods: Using Cre lines that recombine in different subsets of arterial, capillary-venous or endothelial tip cells, we showed that capillary-venous Alk1 deletion was sufficient to induce AVM formation in the postnatal retina. Results: ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1 deficient cells exhibited increased integrin signaling interaction with VEGFR2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacological inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Alk1 deficient mice. Conclusions: Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of AVM formation in HHT disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in HHT patients.

Abstract 448: Etv2-Mir130a-Jarid2 Cascade Regulates Vascular Patterning During Embryogenesis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Bhairab N Singh ◽  
Naoyuki Tahara ◽  
Yasuhiko Kawakami ◽  
Naoko Koyano-Nakagawa ◽  
Wuming Gong ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Critical Role ◽  
Yolk Sac ◽  
Zebrafish Embryos ◽  
Vascular Patterning ◽  
Downstream Target

Remodeling of the pre-existing primitive vasculature is necessary for the formation of a complex branched vascular architecture. However, the factors that modulate these processes are incompletely defined. Previously, we defined the role of microRNAs (miRNAs) in endothelial specification. In the present study, we further examined the Etv2-Cre mediated ablation of Dicer L/L and characterized the perturbed vascular patterning in the embryo proper and yolk-sac. We mechanistically defined an important role for miR-130a , an Etv2 downstream target, in the mediation of vascular patterning and angiogenesis in vitro and in vivo . Inducible overexpression of miR-130a resulted in robust induction of vascular sprouts and angiogenesis with increased uptake of acetylated-LDL. Mechanistically, miR-130a directly regulates Jarid2 expression by binding to its 3’-UTR region. CRISPR/Cas9 mediated knockout of miR-130a showed increased levels of Jarid2 in the ES/EB system. Further, the levels of Jarid2 transcripts were increased in the Etv2-null embryos at E8.5. In the in vivo settings, injection of miR-130a specific morpholinos in zebrafish embryos resulted in perturbed vascular patterning with reduced levels of endothelial transcripts in the miR-130a morphants. qPCR and in situ hybridization techniques demonstrated increased expression of jarid2a in the miR-130a morphants in vivo . These findings demonstrate a critical role for Etv2-miR-130a-Jarid2 in vascular patterning both in vitro and in vivo .

scholarly journals Exploring the Possible Role of Lysine Acetylation onEntamoeba histolyticaVirulence: A Focus on the Dynamics of the Actin Cytoskeleton

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
L. López-Contreras ◽  
V. I. Hernández-Ramírez ◽  
A. E. Lagunes-Guillén ◽  
Sarita Montaño ◽  
B. Chávez-Munguía ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Effective Means ◽  
Cell Movement ◽  
Lysine Acetylation ◽  
Formation Processes ◽  
Severe Impairment ◽  
Cytoskeleton Remodeling ◽  
Cytoskeleton Dynamics

Cytoskeleton remodeling can be regulated, among other mechanisms, by lysine acetylation. The role of acetylation on cytoskeletal and other proteins ofEntamoeba histolyticahas been poorly studied. Dynamic rearrangements of the actin cytoskeleton are crucial for amebic motility and capping formation, processes that may be effective means of evading the host immune response. Here we report the possible effect of acetylation on the actin cytoskeleton dynamics andin vivovirulence ofE. histolytica. Using western blot, immunoprecipitation, microscopy assays, andin silicoanalysis, we show results that strongly suggest that the increase in Aspirin-induced cytoplasm proteins acetylation reduced cell movement and capping formation, likely as a consequence of alterations in the structuration of the actin cytoskeleton. Additionally, intrahepatic inoculation of Aspirin-treated trophozoites in hamsters resulted in severe impairment of the amebic virulence. Taken together, these results suggest an important role for lysine acetylation in amebic invasiveness and virulence.

scholarly journals Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia

Circulation ◽  
2021 ◽  
Author(s):  
Hyojin Park ◽  
Jessica Furtado ◽  
Mathilde Poulet ◽  
Minhwan Chung ◽  
Sanguk Yun ◽  
...  
Keyword(s):  
Blood Flow ◽  
Endothelial Cell ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Nuclear Translocation ◽  
Vascular Malformations ◽  
Critical Role ◽  
Cell Polarization ◽  
Endothelial Cell Migration ◽  
Cardiovascular Development

Background: Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasia (HHT), a devastating disorder that leads to arteriovenous malformations (AVMs). Here we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles. Methods: Using Cre lines that recombine in different subsets of arterial, capillary-venous or endothelial tip cells, we showed that capillary-venous Alk1 deletion was sufficient to induce AVM formation in the postnatal retina. Results: ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro . Mechanistically, ALK1 deficient cells exhibited increased integrin signaling interaction with VEGFR2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacological inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Alk1 deficient mice. Conclusions: Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of AVM formation in HHT disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in HHT patients.

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