Endothelial cells on the move: dynamics in vascular morphogenesis and disease

Fonseca, Catarina G; Barbacena, Pedro; Franco, Cláudio A.

doi:10.1530/vb-20-0007

Cited by 53 publications

(49 citation statements)

References 160 publications

(205 reference statements)

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“…Vascular endothelial growth factor (VEGF) signaling is a master regulator of tip cell biology, and it was shown to regulate endothelial tip cell invasion and sprouting angiogenesis ( 1 , 2 , 12 ). CDC42 and RAC1, downstream of VEGF, are master regulators of endothelial tip cell membrane protrusions ( 13 – 15 ).…”

mentioning

confidence: 99%

Endothelial cell invasion is controlled by dactylopodia

Figueiredo

Barbacena

Russo

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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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.

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mentioning

confidence: 99%

Endothelial cell invasion is controlled by dactylopodia

Figueiredo

Barbacena

Russo

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…During blood vessel formation endothelial junctions play permissive as well as active roles, driving cell rearrangements and cell elongation while maintaining vascular integrity at the same time (Paatero et al, 2018; Sauteur et al, 2014; reviewed by Fonseca et al, 2020; Okuda and Hogan, 2020). Furthermore, endothelial junctions are thought to sense and transmit mechanical forces and thus regulate the collective endothelial response to changes in blood flow or pressure, which occur at the onset of blood flow in a newly formed vessel.…”

Section: Resultsmentioning

confidence: 99%

“…During vascular morphogenesis as well as in functional blood vessels, endothelial cells generate dynamic junctional protrusions, called junction-based lamellipodia (JBL) or junction-associated intermittent lamellipodia (JAIL), which have been observed in different vascular beds of zebrafish embryo as well as mouse embryos and the postnatal retina (reviewed by Cao and Schnittler, 2019; Fonseca et al, 2020). Live-imaging of JBL in zebrafish embryos showed that they are highly dynamic oscillatory structures and are associated with cell movements within the endothelium (Paatero et al, 2018; reviewed by Okuda and Hogan, 2020).…”

Section: Discussionmentioning

confidence: 99%

Vinculin controls endothelial cell junction dynamics during vascular lumen formation

Kotini

Stoel

Han

et al. 2021

Preprint

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Blood 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.

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“…Angiogenesis, defined as the formation of new capillaries from pre-existing blood vessels, is an essential physiological process involved in wound healing, ovulation, vascular and embryonic development [1]. It is a complex process characterized by the migration of endothelial tip and stalk cells in response to a variety of stimuli including chemokines and growth factors such as VEGFA, and is regulated by a variety of signaling pathways [2]. Disordered angiogenesis stimulates a wide range of pathophysiological conditions such as ischemic circulatory disease, cancer, chronic inflammation, atherosclerosis, arthritis and diabetic retinopathy [3].…”

Section: Introductionmentioning

confidence: 99%

Loss of endothelial glucocorticoid receptor promotes angiogenesis via upregulation of Wnt/β-catenin pathway

et al. 2021

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Objective The glucocorticoid receptor (GR) is a member of the nuclear receptor family that controls key biological processes in the cardiovascular system and has recently been shown to modulate Wnt signaling in endothelial cells. Wnt/β-catenin signaling has been demonstrated to be crucial in the process of angiogenesis. In the current study, we studied whether GR could regulate angiogenesis via the Wnt/β-catenin pathway. Approach and Resultsa Key components of the Wnt/β-catenin pathway were evaluated using quantitative PCR and Western blot in the presence or absence of GR. Enhanced angiogenesis was found in GR deficiency in vitro and confirmed with cell viability assays, proliferation assays and tube formation assays. Consistent with these in vitro findings, endothelial cell-specific GR loss GR in vivo promoted angiogenesis in both a hind limb ischemia model and sponge implantation assay. Results were further verified in a novel mouse model lacking endothelial LRP5/6, a key receptor in canonical Wnt signaling, and showed substantially suppressed angiogenesis using these same in vitro and in vivo assays. To further investigate the mechanism of GR regulation of Wnt signaling, autophagy flux was investigated in endothelial cells by visualizing auto phagolysosomes as well as by assessing P62 degradation and LC3B conversion. Results indicated that potentiated autophagy flux participated in GR-Wnt regulation. Conclusions Lack of endothelial GR triggers autophagy flux, leads to activation of Wnt/β-catenin signaling and promotes angiogenesis. There may also be a synergistic interaction between autophagy and Wnt/β-catenin signaling.

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Endothelial cells on the move: dynamics in vascular morphogenesis and disease

Cited by 53 publications

References 160 publications

Endothelial cell invasion is controlled by dactylopodia

Endothelial cell invasion is controlled by dactylopodia

Vinculin controls endothelial cell junction dynamics during vascular lumen formation

Loss of endothelial glucocorticoid receptor promotes angiogenesis via upregulation of Wnt/β-catenin pathway

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