Endothelial Tip Cell Invasive Behaviour During Sprouting Angiogenesis is Controlled by Myosin IIA-Dependent Inhibition of Arp2/3 Activity

2020 ◽  
Author(s):  
Ana M. Figueiredo ◽  
Pedro Barbacena ◽  
Rita Ferreira ◽  
Ana Russo ◽  
Silvia Vaccaro ◽  
...  
Keyword(s):  
Tip Cell ◽  
Sprouting Angiogenesis ◽  
Dependent Inhibition ◽  
Myosin Iia

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.

The histone acetyltransferase HBO1 (KAT7) promotes efficient tip cell sprouting during angiogenesis

Development ◽  
2021 ◽  
Author(s):  
Zoe L. Grant ◽  
Peter F. Hickey ◽  
Waruni Abeysekera ◽  
Lachlan Whitehead ◽  
Sabrina M. Lewis ◽  
...  
Keyword(s):  
Histone Acetyltransferase ◽  
Dynamic Changes ◽  
Cell Behaviour ◽  
Tip Cell ◽  
Sprouting Angiogenesis ◽  
A Genome ◽  
Vessel Growth ◽  
Intergenic Regions ◽  
Tip Cells

Blood vessel growth and remodelling are essential during embryonic development and disease pathogenesis. The diversity of endothelial cells (ECs) is transcriptionally evident and ECs undergo dynamic changes in gene expression during vessel growth and remodelling. Here, we investigated the role of the histone acetyltransferase HBO1 (KAT7), which is important for activating genes during development and histone H3 lysine 14 acetylation (H3K14ac). Loss of HBO1 and H3K14ac impaired developmental sprouting angiogenesis and reduced pathological EC overgrowth in the retinal endothelium. Single-cell RNA-sequencing of retinal ECs revealed an increased abundance of tip cells in Hbo1 deleted retinas, which lead to EC overcrowding in the retinal sprouting front and prevented efficient tip cell migration. We found that H3K14ac was highly abundant in the endothelial genome in both intra- and intergenic regions suggesting that the role of HBO1 is as a genome organiser that promotes efficient tip cell behaviour necessary for sprouting angiogenesis.

scholarly journals A MST1–FOXO1 cascade establishes endothelial tip cell polarity and facilitates sprouting angiogenesis

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yoo Hyung Kim ◽  
Jeongwoon Choi ◽  
Myung Jin Yang ◽  
Seon Pyo Hong ◽  
Choong-kun Lee ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Tip Cell ◽  
Sprouting Angiogenesis

scholarly journals The neuronal transcription factor NPAS4 is a strong inducer of sprouting angiogenesis and tip cell formation

2017 ◽  
Vol 113 (2) ◽  
pp. 222-223 ◽  
Author(s):  
Jennifer Susanne Esser ◽  
Anne Charlet ◽  
Mei Schmidt ◽  
Sophia Heck ◽  
Anita Allen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Formation ◽  
Tip Cell ◽  
Sprouting Angiogenesis

scholarly journals Role of bone morphogenetic proteins in sprouting angiogenesis: differential BMP receptor‐dependent signaling pathways balance stalk vs . tip cell competence

2017 ◽  
Vol 31 (11) ◽  
pp. 4720-4733 ◽  
Author(s):  
Andreas Benn ◽  
Christian Hiepen ◽  
Marc Osterland ◽  
Christof Schütte ◽  
An Zwijsen ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Bone Morphogenetic Proteins ◽  
Tip Cell ◽  
Sprouting Angiogenesis ◽  
Bmp Receptor ◽  
Cell Competence

scholarly journals A Functional Role of S100A4/Non-Muscle Myosin IIA Axis for Pro-Tumorigenic Vascular Functions in Glioblastoma

2021 ◽  
Author(s):  
Madoca Inukai ◽  
Ako Yokoi ◽  
Yuuki Ishizuka ◽  
Miki Hashimura ◽  
Toshihide Matsumoto ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Cell Line ◽  
Hypoxia Inducible Factor ◽  
S100a4 Protein ◽  
S100a4 Expression ◽  
Dependent Inhibition ◽  
Slug Expression ◽  
Myosin Iia ◽  
Muscle Myosin

Abstract Background Glioblastoma (GBM) is the most aggressive form of brain tumor and has vascular-rich features. The S100A4/non-muscle myosin IIA (NMIIA) axis contributes to aggressive phenotypes in a variety of human malignancies, but little is known about its involvement in GBM tumorigenesis. Herein, we examined the role of the S100A4/NMIIA axis during tumor progression and vasculogenesis in GBM Methods We performed immunohistochemistry for S100A4, NMIIA, and two hypoxic markers including hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase 9 (CA9) in samples from 94 GBM cases. The functional impact of S100A4 knockdown and hypoxia were also assessed using a GBM cell line. Results In clinical GBM samples, overexpression of S100A4 and NMIIA was observed in both non-pseudopalisading (Ps) and Ps (-associated) perinecrotic lesions, consistent with stabilization of HIF-1α and CA9. CD34(+) microvascular densities (MVDs) and the interaction of S100A4 and NMIIA were significantly higher in non-Ps perinecrotic lesions compared to those in Ps perinecrotic areas. In non-Ps perinecrotic lesions, S100A4(+)/HIF-1α(-) GBM cells were recruited to the surface of host preexisting vessels in the vascular-rich areas. Elevated vascular endothelial growth factor A (VEGFA) mRNA expression was found in S100A4(+)/HIF-1α(+) GBM cells adjacent to the vascular-rich areas. In addition, GBM patients with high S100A4 protein expression had significantly worse OS and PFS than did patients with low S100A4 expression. Knockdown of S100A4 in the GBM cell line KS-1 decreased migration capability, concomitant with decreased Slug expression; the opposite effects were elicited by blebbistatin-dependent inhibition of NMIIA. Conclusion S100A4(+)/HIF-1α(-) GBM cells are recruited to (and migrate along) preexisting vessels through inhibition of NMIIA activity. This is likely stimulated by extracellular VEGF that is released by S100A4(+)/HIF-1α(+) tumor cells in non-Ps perinecrotic lesions. In turn, these events engender tumor progression via acceleration of pro-tumorigenic vascular functions.

scholarly journals NRP1 acts cell autonomously in endothelium to promote tip cell function during sprouting angiogenesis

Blood ◽  
2013 ◽  
Vol 121 (12) ◽  
pp. 2352-2362 ◽  
Author(s):  
Alessandro Fantin ◽  
Joaquim M. Vieira ◽  
Alice Plein ◽  
Laura Denti ◽  
Marcus Fruttiger ◽  
...  
Keyword(s):  
Cell Function ◽  
Tip Cell ◽  
Sprouting Angiogenesis ◽  
Key Points ◽  
Heterotypic Interactions ◽  
The Brain ◽  
Brain Angiogenesis

Key Points NRP1 promotes brain angiogenesis cell autonomously in endothelium, independently of heterotypic interactions with nonendothelial cells. NRP1 plays a key role in endothelial tip rather than stalk cells during vessel sprouting in the brain.

scholarly journals The endosomal RIN2/Rab5C machinery prevents VEGFR2 degradation to control gene expression and tip cell identity during angiogenesis

Angiogenesis ◽  
2021 ◽  
Author(s):  
Lanette Kempers ◽  
Yuki Wakayama ◽  
Ivo van der Bijl ◽  
Charita Furumaya ◽  
Iris M. De Cuyper ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Genes ◽  
Cell Formation ◽  
Stalk Cell ◽  
Vegf Receptor ◽  
Tip Cell ◽  
Sprouting Angiogenesis ◽  
Vegf Signaling

AbstractSprouting angiogenesis is key to many pathophysiological conditions, and is strongly regulated by vascular endothelial growth factor (VEGF) signaling through VEGF receptor 2 (VEGFR2). Here we report that the early endosomal GTPase Rab5C and its activator RIN2 prevent lysosomal routing and degradation of VEGF-bound, internalized VEGFR2 in human endothelial cells. Stabilization of endosomal VEGFR2 levels by RIN2/Rab5C is crucial for VEGF signaling through the ERK and PI3-K pathways, the expression of immediate VEGF target genes, as well as specification of angiogenic ‘tip’ and ‘stalk’ cell phenotypes and cell sprouting. Using overexpression of Rab mutants, knockdown and CRISPR/Cas9-mediated gene editing, and live-cell imaging in zebrafish, we further show that endosomal stabilization of VEGFR2 levels is required for developmental angiogenesis in vivo. In contrast, the premature degradation of internalized VEGFR2 disrupts VEGF signaling, gene expression, and tip cell formation and migration. Thus, an endosomal feedforward mechanism maintains receptor signaling by preventing lysosomal degradation, which is directly linked to the induction of target genes and cell fate in collectively migrating cells during morphogenesis.

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