scholarly journals Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice

Blood ◽  
2011 ◽  
Vol 118 (12) ◽  
pp. 3436-3439 ◽  
Author(s):  
Hasina H. Outtz ◽  
Ian W. Tattersall ◽  
Natalie M. Kofler ◽  
Nicole Steinbach ◽  
Jan Kitajewski
Keyword(s):  
Endothelial Cell ◽  
Notch Signaling ◽  
Leading Edge ◽  
Vascular Differentiation ◽  
Vascular Integrity ◽  
Sprouting Angiogenesis ◽  
Macrophage Recruitment ◽  
Reporter Mice ◽  
Retinal Angiogenesis ◽  
Tip Cells

Abstract Notch is a critical regulator of angiogenesis, vascular differentiation, and vascular integrity. We investigated whether Notch signaling affects macrophage function during retinal angiogenesis in mice. Retinal macrophage recruitment and localization in mice with myeloid-specific loss of Notch1 was altered, as these macrophages failed to localize at the leading edge of the vascular plexus and at vascular branchpoints. Furthermore, these retinas were characterized by elongated endothelial cell sprouts that failed to anastomose with neighboring sprouts. Using Notch reporter mice, we demonstrate that retinal macrophages localize between Dll4-positive tip cells and at vascular branchpoints, and that these macrophages had activated Notch signaling. Taken together, these data demonstrate that Notch signaling in macrophages is important for their localization and interaction with endothelial cells during sprouting angiogenesis.

scholarly journals Vinculin controls endothelial cell junction dynamics during vascular lumen formation

2021 ◽  
Author(s):  
Maria P. Kotini ◽  
Miesje M. van der Stoel ◽  
Mitchell K. Han ◽  
Bettina Kirchmaier ◽  
Johan de Rooij ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Junctions ◽  
Cell Junction ◽  
Vascular Integrity ◽  
Lumen Formation ◽  
Cell Behaviors ◽  
Sprouting Angiogenesis ◽  
Dynamic Cell ◽  
External Forces ◽  
Cell Cell

AbstractBlood vessel morphogenesis is driven by coordinated endothelial cell behaviors, which depend on dynamic cell-cell interactions. Remodeling of endothelial cell-cell junctions promote morphogenetic cellular events while preserving vascular integrity. Here, we have analyzed the dynamics of endothelial cell-cell junctions during lumen formation in angiogenic sprouts. By live-imaging of the formation of intersegmental blood vessels in zebrafish, we demonstrate that lumen expansion is accompanied by the formation of transient finger-shaped junctions. Formation and maintenance of these junctional fingers are positively regulated by blood pressure whereas inhibition of blood flow prevents their formation. Using fluorescent reporters, we show that the tension-sensor Vinculin localizes to junctional fingers. Furthermore, loss of vinculin function, in vinculin a and -b double knockouts, prevents junctional finger formation in angiogenic sprouts, whereas endothelial expression of a vinculin transgene is sufficient to restore junctional fingers. Taken together, our findings suggest a mechanism in which lumen expansion during angiogenesis leads to an increase in junctional tension, which triggers recruitment of vinculin and formation of junctional fingers. We propose that endothelial cells may employ force-dependent junctional remodeling to react to changes in external forces to protect cell-cell contacts and to maintain vascular integrity during sprouting angiogenesis.

scholarly journals Endothelial cell invasiveness is controlled by myosin IIA-dependent inhibition of Arp2/3 activity

2020 ◽  
Author(s):  
Ana M. Figueiredo ◽  
Pedro Barbacena ◽  
Ana Russo ◽  
Silvia Vaccaro ◽  
Daniela Ramalho ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Focal Adhesions ◽  
Sprouting Angiogenesis ◽  
Dependent Inhibition ◽  
Myosin Iia ◽  
Maturation State ◽  
Cell Invasiveness ◽  
Cellular Protrusion ◽  
Tip Cells ◽  
New Strategies

AbstractSprouting angiogenesis is fundamental for development and contributes to multiple diseases, including cancer, diabetic retinopathy and cardiovascular diseases. Sprouting angiogenesis depends on the invasive properties of endothelial tip cells. However, there is very limited knowledge on the mechanisms that endothelial tip cells use to invade into tissues. Here, we prove that endothelial tip cells use long lamellipodia projections (LLPs) as the main cellular protrusion for invasion into non-vascular extracellular matrix. We show that LLPs and filopodia protrusions are balanced by myosin-IIA (MIIA) and actin-related protein 2/3 (Arp2/3) activity. Endothelial cell-autonomous ablation of MIIA promotes excessive LLPs formation in detriment of filopodia. Conversely, endothelial cell-autonomous ablation of Arp2/3 prevents LLPs development and leads to excessive filopodia formation. We further show that MIIA inhibits Rac1-dependent activation of Arp2/3, by regulating the maturation state of focal adhesions. Our discoveries establish the first comprehensive model of how endothelial tip cells regulate its protrusive activity and will pave the way towards new strategies to block invasive tip cells during sprouting angiogenesis.

scholarly journals The Transcription Factor Complex LMO2/TAL1 Regulates Branching and Endothelial Cell Migration in Sprouting Angiogenesis

2021 ◽  
Author(s):  
Yoshihiro Yamada ◽  
Yi Zhong ◽  
Shiho Miki ◽  
Akiko Taura ◽  
Terence Rabbitts
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Endothelial Cell ◽  
Endothelial Cell Migration ◽  
Angiogenic Switch ◽  
Sprouting Angiogenesis ◽  
Relative Paucity ◽  
Angiopoietin 2 ◽  
Tip Cells ◽  
Transcription Factor Complex

Abstract The transcription factor complex, consisting of LMO2, TAL1/LYL1, and GATA2, plays an important role in capillary sprouting by regulating VEGFR2, DLL4, and angiopoietin 2 in tip cells. Overexpression of the basic helix-loophelix transcription factor LYL1 in transgenic mice results in shortened tails. This phenotype is associated with vessel hyperbranching and a relative paucity of straight vessels due to DLL4 downregulation in tip cells by forming aberrant complex consisting of LMO2 and LYL1. Knockdown of LMO2 or TAL1 inhibits capillary sprouting in spheroid-based angiogenesis assays, which is associated with decreased angiopoietin 2 secretion. In the same assay using mixed TAL1- and LYL1-expressing endothelial cells, TAL1 was found to be primarily located in tip cells, while LYL1-expressing cells tended to occupy the stalk position in sprouts by upregulating VEGFR1 than TAL1. Thus, the interaction between LMO2 and TAL1 in tip cells plays a key role in angiogenic switch of sprouting angiogenesis.

scholarly journals eNOS controls angiogenic sprouting and retinal neovascularization through the regulation of endothelial cell polarity

2021 ◽  
Author(s):  
Tracy L. Smith ◽  
Malika Oubaha ◽  
Gael Cagnone ◽  
Cécile Boscher ◽  
Jin Sung Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Polarity ◽  
Cell Polarization ◽  
No Synthase ◽  
Sprouting Angiogenesis ◽  
Oxygen Induced Retinopathy ◽  
Tip Cells ◽  
Deficient Mice ◽  
Vascular Branching

AbstractThe roles of nitric oxide (NO) and endothelial NO synthase (eNOS) in the regulation of angiogenesis are well documented. However, the involvement of eNOS in the sprouting of endothelial tip-cells at the vascular front during sprouting angiogenesis remains poorly defined. In this study, we show that downregulation of eNOS markedly inhibits VEGF-stimulated migration of endothelial cells but increases their polarization, as evidenced by the reorientation of the Golgi in migrating monolayers and by the fewer filopodia on tip cells at ends of sprouts in endothelial cell spheroids. The effect of eNOS inhibition on EC polarization was prevented in Par3-depleted cells. Importantly, downregulation of eNOS increased the expression of polarity genes, such as PARD3B, PARD6A, PARD6B, PKCΖ, TJP3, and CRB1 in endothelial cells. In retinas of eNOS knockout mice, vascular development is retarded with decreased vessel density and vascular branching. Furthermore, tip cells at the extremities of the vascular front have a marked reduction in the number of filopodia per cell and are more oriented. In a model of oxygen-induced retinopathy (OIR), eNOS deficient mice are protected during the initial vaso-obliterative phase, have reduced pathological neovascularization, and retinal endothelial tip cells have fewer filopodia. Single-cell RNA sequencing of endothelial cells from OIR retinas revealed enrichment of genes related to cell polarity in the endothelial tip-cell subtype of eNOS deficient mice. These results indicate that inhibition of eNOS alters the polarity program of endothelial cells, which increases cell polarization, regulates sprouting angiogenesis and normalizes pathological neovascularization during retinopathy.

scholarly journals Endothelial cell invasion is controlled by dactylopodia

2021 ◽  
Vol 118 (18) ◽  
pp. e2023829118
Author(s):  
Ana Martins Figueiredo ◽  
Pedro Barbacena ◽  
Ana Russo ◽  
Silvia Vaccaro ◽  
Daniela Ramalho ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cell ◽  
Cell Invasion ◽  
Focal Adhesions ◽  
Comprehensive Model ◽  
Related Protein ◽  
Sprouting Angiogenesis ◽  
Maturation State ◽  
Cellular Protrusion ◽  
Tip Cells

Sprouting angiogenesis is fundamental for development and contributes to cancer, diabetic retinopathy, and cardiovascular diseases. Sprouting angiogenesis depends on the invasive properties of endothelial tip cells. However, there is very limited knowledge on how tip cells invade into tissues. Here, we show that endothelial tip cells use dactylopodia as the main cellular protrusion for invasion into nonvascular extracellular matrix. We show that dactylopodia and filopodia protrusions are balanced by myosin IIA (NMIIA) and actin-related protein 2/3 (Arp2/3) activity. Endothelial cell-autonomous ablation of NMIIA promotes excessive dactylopodia formation in detriment of filopodia. Conversely, endothelial cell-autonomous ablation of Arp2/3 prevents dactylopodia development and leads to excessive filopodia formation. We further show that NMIIA inhibits Rac1-dependent activation of Arp2/3 by regulating the maturation state of focal adhesions. Our discoveries establish a comprehensive model of how endothelial tip cells regulate its protrusive activity and will pave the way toward strategies to block invasive tip cells during sprouting angiogenesis.

scholarly journals Nerve growth factor regulates endothelial cell survival and pathological retinal angiogenesis

2019 ◽  
Vol 23 (4) ◽  
pp. 2362-2371 ◽  
Author(s):  
Maria Troullinaki ◽  
Vasileia‐Ismini Alexaki ◽  
Ioannis Mitroulis ◽  
Anke Witt ◽  
Anne Klotzsche–von Ameln ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Cell Survival ◽  
Nerve Growth ◽  
Endothelial Cell Survival ◽  
Retinal Angiogenesis

scholarly journals Endothelial Cell mTOR Complex-2 Regulates Sprouting Angiogenesis

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0135245 ◽  
Author(s):  
Maikel A. Farhan ◽  
Katia Carmine-Simmen ◽  
John D. Lewis ◽  
Ronald B. Moore ◽  
Allan G. Murray
Keyword(s):  
Endothelial Cell ◽  
Sprouting Angiogenesis

scholarly journals LRP1 Regulates Retinal Angiogenesis by Inhibiting PARP-1 Activity and Endothelial Cell Proliferation

2016 ◽  
Vol 36 (2) ◽  
pp. 350-360 ◽  
Author(s):  
Hua Mao ◽  
Pamela Lockyer ◽  
W.H. Davin Townley-Tilson ◽  
Liang Xie ◽  
Xinchun Pi
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Endothelial Cell Proliferation ◽  
Retinal Angiogenesis ◽  
Parp 1

Abstract 3640: Mitochondrial Uncoupling Protein 2 Facilitates Endothelial Cell Growth and Angiogenesis via Reduction of Mitochondrial Superoxide

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yukio Shimasaki ◽  
Kai Chen ◽  
John F Keaney
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Growth ◽  
Mitochondrial Function ◽  
Endothelial Cell Proliferation ◽  
Wild Type ◽  
Sprouting Angiogenesis ◽  
Mitochondrial Superoxide ◽  
Endothelial Cell Growth ◽  
Aortic Explants

Background: Growing evidence suggests that mitochondrial function contributes to cell phenotype. One important component of mitochondrial function is the membrane potential that is controlled, in part, by uncoupling proteins (UCPs). Based on our previous data, the UCP2 is predominantly expressed in cultured endothelial cells. Therefore, we sought to examine the role of UCP2 in endothelial cell growth and angiogenesis. Methods and Results: Murine lung endothelial cells (MLECs) were isolated from UCP2-null and wild-type mice. UCP2-null cells were found less proliferative than wild-type cells (P<0.02, UCP2-null cells vs. wild-type cells, n=4). This defect of UCP2-null cells was rescued by UCP2 adenovirus transfection (19% increase, p<0.02 vs. LacZ adenovirus treated cells, n=3), and also rescued by transfection with manganese superoxide dismutase (MnSOD) adenovirus (53% increase, P<0.002 vs. LacZ adenovirus treated cells, n=3). We found a reciprocal relation such as no UCP2 expression and higher mitochondrial superoxide level in the MLECs (P<0.005, UCP2-null cells vs. wild-type cells, n=3), suggesting that mitochondrial superoxide may regulate endothelial cell growth. Then, we prepared murine aortic rings from UCP2-null and wild-type mice and embedded in rat tail collagen gel. The sprouting angiogenesis of UCP2-null explants was significantly less than wild-type explants (P<0.02, UCP2-null explants vs. wild-type explants, n=3– 4). Furthermore, MLECs from MnSOD-heterozygous mice showed less proliferation with lower expression of UCP2 protein and higher mitochondrial superoxide level compared to the MLECs from wild-type littermates (P<0.02, MnSOD-heterozygous cells vs. wild-type cells, n=4 – 8). We also observed less sprouting angiogenesis in MnSOD-heterozygous aortic explants than wild-type aortic explants (P<0.05, MnSOD-heterozygous explants vs. wild-type explants, n=3– 6). Conclusions: These data indicate that mitochondrial superoxide controls endothelial cell proliferation and angiogenesis, suggesting that mitochondrial metabolism modulates the endothelial cell growth and angiogenesis.

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