scholarly journals FOXO1 represses Sprouty2 and Sprouty4 expression in endothelial cells to promote arterial specification and vascular remodeling in the mouse yolk sac

2021 ◽  
Author(s):  
Nanbing Li-Villarreal ◽  
Rebecca Lee Yean Wong ◽  
Monica D Garcia ◽  
Ryan S Udan ◽  
Ross A. Poche ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Remodeling ◽  
Circulatory System ◽  
Yolk Sac ◽  
Null Mouse ◽  
Regulatory Regions ◽  
Over Expression ◽  
Vessel Remodeling ◽  
Transgenic Embryos ◽  
Post Implantation

The establishment of a functional circulatory system is required for post-implantation development during mouse embryogenesis. Previous studies in null mouse models have reported that FOXO1, a Forkhead family transcription factor, is essential for yolk sac vascular remodeling and survival beyond embryonic day (E) 11. Here, we show that loss of FoxO1 in E8.25 endothelial cells results in increased Sprouty2 and Sprouty4 gene expression, reduced expression of arterial genes, and reduced Flk1/Vegfr2 expression without affecting overall endothelial cell identity, survival or proliferation. Using Dll4-BAC-nlacZ reporter, we found that one of the earliest expressed arterial genes, Dll4, is significantly reduced in the yolk sac of FoxO1 mutants without being substantially affected in the embryo. We show that in the yolk sac, FOXO1 not only binds directly to a subset of previously identified activating Sprouty2 regulatory regions and newly identified conserved Sprouty4 regulatory regions, but can also repress their expression. Additionally, over expression of Sprouty4 in E8.25 transient transgenic embryos largely recapitulates reduced expression of arterial genes seen in endothelial FoxO1 mutants. These data reveal a novel role for FOXO1 as a key transcriptional repressor in early, pre-flow arterial specification and subsequent vessel remodeling within the murine yolk sac.

scholarly journals Vascular remodeling is governed by a VEGFR3-dependent fluid shear stress set point

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Nicolas Baeyens ◽  
Stefania Nicoli ◽  
Brian G Coon ◽  
Tyler D Ross ◽  
Koen Van den Dries ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Vascular Remodeling ◽  
Fluid Shear Stress ◽  
Umbilical Vein ◽  
Fluid Shear ◽  
Set Point ◽  
Vessel Remodeling ◽  
Umbilical Vein Endothelial Cells

Vascular remodeling under conditions of growth or exercise, or during recovery from arterial restriction or blockage is essential for health, but mechanisms are poorly understood. It has been proposed that endothelial cells have a preferred level of fluid shear stress, or ‘set point’, that determines remodeling. We show that human umbilical vein endothelial cells respond optimally within a range of fluid shear stress that approximate physiological shear. Lymphatic endothelial cells, which experience much lower flow in vivo, show similar effects but at lower value of shear stress. VEGFR3 levels, a component of a junctional mechanosensory complex, mediate these differences. Experiments in mice and zebrafish demonstrate that changing levels of VEGFR3/Flt4 modulates aortic lumen diameter consistent with flow-dependent remodeling. These data provide direct evidence for a fluid shear stress set point, identify a mechanism for varying the set point, and demonstrate its relevance to vessel remodeling in vivo.

Hedgehog is required for murine yolk sac angiogenesis

Development ◽  
2002 ◽  
Vol 129 (2) ◽  
pp. 361-372 ◽  
Author(s):  
Noah Byrd ◽  
Sandy Becker ◽  
Peter Maye ◽  
Roopa Narasimhaiah ◽  
Benoit St-Jacques ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Vascular Remodeling ◽  
Hedgehog Signaling ◽  
Es Cells ◽  
Embryonic Stem ◽  
Yolk Sac ◽  
Embryoid Bodies ◽  
Visceral Endoderm

Blood islands, the precursors of yolk sac blood vessels, contain primitive erythrocytes surrounded by a layer of endothelial cells. These structures differentiate from extra-embryonic mesodermal cells that underlie the visceral endoderm. Our previous studies have shown that Indian hedgehog (Ihh) is expressed in the visceral endoderm both in the visceral yolk sac in vivo and in embryonic stem (ES) cell-derived embryoid bodies. Differentiating embryoid bodies form blood islands, providing an in vitro model for studying vasculogenesis and hematopoiesis. A role for Ihh in yolk sac function is suggested by the observation that roughly 50% of Ihh–/– mice die at mid-gestation, potentially owing to vascular defects in the yolk sac. To address the nature of the possible vascular defects, we have examined the ability of ES cells deficient for Ihh or smoothened (Smo), which encodes a receptor component essential for all hedgehog signaling, to form blood islands in vitro. Embryoid bodies derived from these cell lines are unable to form blood islands, and express reduced levels of both PECAM1, an endothelial cell marker, and α-SMA, a vascular smooth muscle marker. RT-PCR analysis in the Ihh–/– lines shows a substantial decrease in the expression of Flk1 and Tal1, markers for the hemangioblast, the precursor of both blood and endothelial cells, as well as Flt1, an angiogenesis marker. To extend these observations, we have examined the phenotypes of embryo yolk sacs deficient for Ihh or Smo. Whereas Ihh–/– yolk sacs can form blood vessels, the vessels are fewer in number and smaller, perhaps owing to their inability to undergo vascular remodeling. Smo–/– yolk sacs arrest at an earlier stage: the endothelial tubes are packed with hematopoietic cells, and fail to undergo even the limited vascular remodeling observed in the Ihh–/– yolk sacs. Our study supports a role for hedgehog signaling in yolk sac angiogenesis.

scholarly journals Dynamic responses of endothelial cells to changes in blood flow during vascular remodeling of the mouse yolk sac

Development ◽  
2013 ◽  
Vol 140 (19) ◽  
pp. 4041-4050 ◽  
Author(s):  
Ryan S. Udan ◽  
Tegy J. Vadakkan ◽  
Mary E. Dickinson
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Vascular Remodeling ◽  
Yolk Sac ◽  
Dynamic Responses

scholarly journals The transcription factor FoxO1 is required in endothelial cells for vascular remodeling of the mouse yolk sac

2011 ◽  
Vol 356 (1) ◽  
pp. 145
Author(s):  
Monica D. Garcia ◽  
Tiffany M. Sills ◽  
Ryan S. Udan ◽  
Tegy J. Vadakkan ◽  
Ronald A. DePinho ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Vascular Remodeling ◽  
Yolk Sac

Inhibition of hypoxia-inducible factor activity in endothelial cells disrupts embryonic cardiovascular development

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 584-590 ◽  
Author(s):  
Alexander H. Licht ◽  
Felix Müller-Holtkamp ◽  
Ingo Flamme ◽  
Georg Breier
Keyword(s):  
Endothelial Cells ◽  
Blood Vessel ◽  
Vascular Remodeling ◽  
Cellular Response ◽  
Dominant Negative ◽  
Cardiovascular Development ◽  
Low Oxygen ◽  
Angiogenic Growth Factors ◽  
Transcriptional Responses ◽  
Transgenic Embryos

AbstractHypoxia-inducible factors (HIFs) are transcriptional regulators that mediate the cellular response to low oxygen levels. By stimulating the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF), they trigger the neovascularization of tissues under physiologic and pathologic conditions. Here, we have investigated the endothelial cell–autonomous HIF function in blood vessel growth and development by expressing a dominant-negative HIF mutant (HIFdn) that inhibits the transcriptional responses mediated by both HIF-1 and HIF-2, specifically in endothelial cells of transgenic mice. HIFdn transgenic embryos were growth retarded and died around E11.5. Primitive vascular networks were established, but vascular remodeling in the yolk sac and in the embryo proper was defective, and vascular sprouts failed to invade the neuroepithelium. In addition, heart looping was incomplete, and the ventricles of the heart were thin-walled and lacked trabeculation. Similar cardiovascular defects have been observed in Tie2–deficient mouse embryos. Consistently, HIFdn transgenic embryos expressed reduced levels of the endothelial angiopoietin receptor, Tie-2, whereas other endothelial markers, such as PECAM-1, Tie-1, and VE-cadherin were not affected. These results show that HIFs in endothelial cells are essential for embryonic heart and blood vessel development and control angiogenesis and vascular remodeling.

scholarly journals Studying dynamic stress effects on the behaviour of THP-1 cells by microfluidic channels

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Semra Zuhal Birol ◽  
Rana Fucucuoglu ◽  
Sertac Cadirci ◽  
Ayca Sayi-Yazgan ◽  
Levent Trabzon
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Vascular System ◽  
Circulatory System ◽  
Disease Process ◽  
Microfluidic Channels ◽  
Shear Stresses ◽  
Stress Effects ◽  
Adhesion Behavior ◽  
Cycling System

AbstractAtherosclerosis is a long-term disease process of the vascular system that is characterized by the formation of atherosclerotic plaques, which are inflammatory regions on medium and large-sized arteries. There are many factors contributing to plaque formation, such as changes in shear stress levels, rupture of endothelial cells, accumulation of lipids, and recruitment of leukocytes. Shear stress is one of the main factors that regulates the homeostasis of the circulatory system; therefore, sudden and chronic changes in shear stress may cause severe pathological conditions. In this study, microfluidic channels with cavitations were designed to mimic the shape of the atherosclerotic blood vessel, where the shear stress and pressure difference depend on design of the microchannels. Changes in the inflammatory-related molecules ICAM-1 and IL-8 were investigated in THP-1 cells in response to applied shear stresses in an continuous cycling system through microfluidic channels with periodic cavitations. ICAM-1 mRNA expression and IL-8 release were analyzed by qRT-PCR and ELISA, respectively. Additionally, the adhesion behavior of sheared THP-1 cells to endothelial cells was examined by fluorescence microscopy. The results showed that 15 Pa shear stress significantly increases expression of ICAM-1 gene and IL-8 release in THP-1 cells, whereas it decreases the adhesion between THP-1 cells and endothelial cells.

scholarly journals Blood flow boosts BMP signaling to keep vessels in shape

2016 ◽  
Vol 214 (7) ◽  
pp. 793-795 ◽  
Author(s):  
Claudio A. Franco ◽  
Holger Gerhardt
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Blood Flow ◽  
Vascular Remodeling ◽  
Bmp Signaling ◽  
Mural Cells ◽  
Bone Morphogenic Proteins ◽  
Cell Biol ◽  
Suppress Cell Proliferation

Bone morphogenic proteins (BMPs) and blood flow regulate vascular remodeling and homeostasis. In this issue, Baeyens et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201603106) show that blood flow sensitizes endothelial cells to BMP9 signaling by triggering Alk1/ENG complexing to suppress cell proliferation and to recruit mural cells, thereby establishing endothelial quiescence.

scholarly journals Galectin-3- Mediated Transdifferentiation of Pulmonary Artery Endothelial Cells Contributes to Hypoxic Pulmonary Vascular Remodeling

2018 ◽  
Vol 51 (2) ◽  
pp. 763-777 ◽  
Author(s):  
Li Zhang ◽  
Yu-mei Li ◽  
Xi-xi Zeng ◽  
Xiao-yan Wang ◽  
Shao-kun Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Pulmonary Artery ◽  
Ultrasound Biomicroscopy ◽  
Pulmonary Artery Hypertension ◽  
Carbohydrate Binding ◽  
Vessel Remodeling ◽  
Galectin 3

Background/Aims: Vascular muscularity is a key event in vessel remodeling during pulmonary artery hypertension (PAH). Endothelial-mesenchymal transdifferentiation (EndMT) has been increasingly reported to play a role in disease occurrence. Galectin-3, a carbohydrate-binding protein regulates cell proliferation, differentiation, migration and neovascularization. However, whether galectin-3 controls endothelial cell transdifferentiation during the development of PAH is unknown. Methods: Rats were exposed to normoxic or hypoxic conditions (fraction of inspired O2 0.10) for 21 d to establish PAH models. Hemodynamic changes were evaluated through surgery of the right jugular vein and ultrasound biomicroscopy inviVue. And vessel pathological alterations were detected by H&E staining. Galectin-3 (Gal-3)-induced pulmonary artery endothelium cell (PAEC) dynamic alterations were measured by MTT assays, Cell immunofluorescence, Flow cytometry, Real-time PCR and Western blot. Results: Our study demonstrated that Gal-3 was expressed in hypoxic pulmonary vascular adventitia and intima. The increased Gal-3 expression was responsible for hypoxic vessel remodeling and PAH development in vivo. Gal-3 was found to inhibit cell proliferation and apoptosis in cultured endothelial cells. Meanwhile endothelial cell morphology was altered and exhibited smooth muscle-like cell features as demonstrated by the expression of α-SMA after Gal-3 treatment. Gal-3 activated Jagged1/Notch1 pathways and induced MyoD and SRF. When MyoD or SRF were silenced with siRNAs, Gal-3-initiated transdifferentiation in endothelial cells was blocked as indicated by a lack of α-SMA. Conclusion: These results suggest that Gal-3 induces PAECs to acquire an α-SMA phenotype via a transdifferentiation process which depends on the activation of Jagged1/Notch1 pathways that mediate MyoD and SRF expression.

Abstract P241: Calpain-1 Is Increased in Mitochondria and Contributes to Mitochondrial ROS Generation in High Glucose--Stimulated Endothelial Cells and Endothelial Dysfunction in Mouse Models of Diabetes

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Qing Zhao ◽  
Futian Tang ◽  
Limei Shan ◽  
Inga Cepinskas ◽  
Gedas Cepinskas ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
High Glucose ◽  
Aortic Ring ◽  
Ros Generation ◽  
Type I ◽  
Ros Production ◽  
Diabetic Mice ◽  
Calpain Activity ◽  
Over Expression ◽  
Mitochondrial Ros

Objectives: Elevated levels of reactive oxygen species (ROS) are the initial source of endothelial dysfunction in diabetes. Calpain has been implicated in diabetic vascular complications. The present study was to investigate the role of calpain in mitochondrial ROS generation in endothelial cells and vascular dysfunction in diabetic mice. Methods: Endothelial cells cultured from human umbilical vein (HUVEC) were stimulated with high glucose. Calpain activity and protein were determined in mitochondria of HUVEC. Intracellular and mitochondrial ROS generation as well as apoptosis were measured. Type I diabetic OVE 26 mice and type II diabetic db/db mice with calpastatin over-expression (OVE26/CAST and db/db-CAST) were generated, respectively. Type I diabetes was also induced in both wild-type and Tg-CAST mice by injection of streptozocin (STZ). The endothelium-dependent relaxation of aortic ring was measured. Results: High glucose significantly increased calpain-1 protein, calpain activity and ROS generation in mitochondria of HUVEC. Pharmacological inhibition of calpain or over-expression of calpastatin abrogated high glucose-induced intracellular ROS production, mitochondrial ROS generation and apoptosis in HUVEC. Incubation of isolated mitochondria with calpain-1 protein significantly induced its ROS generation and the membrane potential. In diabetic mice, calpain activity was induced in aortic vessels, which correlated with an increase in ROS production and protein tyrosine nitration. Over-expression of calpastatin prevented calpain activity, reduced ROS production and inhibited protein tyrosine nitration in diabetic mice. Aortic ring segments from diabetic mice exhibited a significant reduction in vascular relaxation to acetylcholine, which was reversed by over-expression of calpastatin in Tg-CAST, OVE26/CAST and db/db-CAST mice. Conclusions: This study has demonstrated a novel role of calpain in mitochondrial ROS generation, which contributes to apoptosis in endothelial cells during hyperglycemia. Thus, over-expression of calpastatin inhibits reduces ROS production and ameliorates endothelium-dependent vascular dysfunction in mouse models of diabetes.

Abstract 535: Trem Like Transcript-1 (TLT-1) Regulates Both Leukocytes and Endothelial Cells to Mediate Immunohemostasis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
A. V Washington
Keyword(s):  
Endothelial Cells ◽  
Platelet Activation ◽  
Therapeutic Interventions ◽  
Soluble Form ◽  
Null Mouse ◽  
Aortic Sinus ◽  
Vascular Integrity ◽  
Vessel Growth ◽  
Lewis Lung Carcinoma Model ◽  
Progression Of Atherosclerosis

TLT-1 is a 35kd receptor stored in the α-granules of platelets and released upon platelet activation like p-selectin. A soluble form is also released. A case has been made that the protein or proteins that regulate inflammatory bleeding is stored in the platelet α-granules. We hypothesized that TLT-1 is one of these proteins and we investigated TLT-1’s role in inflammatory bleeding. Using two different models of inflammation and three different models of transmigration we show that TLT-1 mediates neutrophil transmigration across the vessel wall. In the absence of TLT-1 transmigration leads to bleeding that can be partially rescued by soluble TLT-1 (sTLT-1: see poster J. Morales). Based on these results we hypothesized that TLT-1 enhances the progression of atherosclerosis and cancer. To test this hypothesis we crossed the treml1 -/- mice with apoe -/- mice creating the DKO mouse and evaluated lesion progression over 20 weeks. Our results demonstrate that the DKO has significantly less lesions in the aortic sinus than their littermate controls (n=8/group; p <0.05). The smaller lesions are associated with less platelet activation and fewer platelet-leukocyte conjugates. Parallel studies investigating TLT-1 in the α-granules revealed a significant co-localization with pro-angiogenic VEGF and higher sTLT-1 release with PAR1 vs PAR4 platelet activation; suggestive of a role for TLT-1 in angiogenesis. We subsequently asked if, “sTLT-1 has an effect on endothelial cells?” We show angiogenic effects of sTLT-1 on HUVECs that is blocked by the addition of anti-TLT-1, demonstrating it’s a sTLT-1 mediated process. Further studies using the Lewis lung carcinoma model demonstrate that the tumors in the null mouse have significantly fewer vessels than wildtype tumors and lower infiltration of macrophages (n=15). We subsequently show that sTLT-1 partially rescues the phenotype by increasing macrophage infiltration and increasing vessel growth (n=13) and that antibodies to TLT-1 recapitulate the treml1 -/- phenotype (n=10) suggesting anti-TLT-1 may be used as an intervention. We conclude that TLT-1 regulates both leukocytes and endothelial cells to mediate vascular integrity and is a plausible target for therapeutic interventions in cancer and atherosclerosis.

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