Integrin-dependent and -independent functions of astrocytic fibronectin in retinal angiogenesis

Stenzel, Denise; Lundkvist, Andrea; Sauvaget, Dominique; Busse, Marta; Graupera, Mariona; Flier, Arjan van der; Wijelath, Errol S.; Murray, Jacqueline; Sobel, Michael; Costell, Mercedes; Takahashi, Seiichiro; Fässler, Reinhard; Yamaguchi, Yu; Gutmann, David H.; Hynes, Richard O.; Gerhardt, Holger

doi:10.1242/dev.071381

Cited by 128 publications

(148 citation statements)

References 47 publications

(79 reference statements)

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“…However, the survival of these global and constitutive mutants is distinct from the lethality of Itgb1 iECKO mice, suggesting involvement of other matrix molecules. Fibronectin binding to a5b1 heterodimers mediates the adhesion of endothelial filopodia to astrocytic matrix 44 . EC-specific targeting of the a5 and av integrins, the major fibronectin receptors in the endothelium, led to the formation of oedema but did not substantially impair angiogenesis in the embryo 45 .…”

Section: Discussionmentioning

confidence: 99%

Integrin β1 controls VE-cadherin localization and blood vessel stability

et al. 2015

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Angiogenic blood vessel growth requires several distinct but integrated cellular activities. Endothelial cell sprouting and proliferation lead to the expansion of the vasculature and give rise to a highly branched, immature plexus, which is subsequently reorganized into a mature and stable network. Although it is known that integrin-mediated cell-matrix interactions are indispensable for embryonic angiogenesis, little is known about the function of integrins in different steps of vascular morphogenesis. Here, by investigating the integrin b1-subunit with inducible and endothelial-specific gene targeting in the postnatal mouse retina, we show that b1 integrin promotes endothelial sprouting but is a negative regulator of proliferation. In maturing vessels, integrin b1 is indispensable for proper localization of VE-cadherin and thereby cell-cell junction integrity. The sum of our findings establishes that integrin b1 has critical functions in the growing and maturing vasculature, and is required for the formation of stable, non-leaky blood vessels.

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Section: Discussionmentioning

confidence: 99%

Integrin β1 controls VE-cadherin localization and blood vessel stability

et al. 2015

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“…In the retina, FN deposited by astrocytes localized VEGF-A ahead of migrating tip cells in angiogenic sprouts (27). Interestingly, VEGF-A is highly expressed in e14.5 embryonic pituitaries (GenePaint.org) and has been implicated in vascular development in the mouse pituitary gland (28).…”

Section: Rna-sequencing Identified An Integrin β1-dependent Transcripmentioning

confidence: 99%

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland

Scully

Skowronska‐Krawczyk

Krawczyk

et al. 2016

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

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As a key component of the vertebrate neuroendocrine system, the pituitary gland relies on the progressive and coordinated development of distinct hormone-producing cell types and an invading vascular network. The molecular mechanisms that drive formation of the pituitary vasculature, which is necessary for regulated synthesis and secretion of hormones that maintain homeostasis, metabolism, and endocrine function, remain poorly understood. Here, we report that expression of integrin β1 in embryonic pituitary epithelial cells is required for angiogenesis in the developing mouse pituitary gland. Deletion of pituitary epithelial integrin β1 before the onset of angiogenesis resulted in failure of invading endothelial cells to recruit pericytes efficiently, whereas deletion later in embryogenesis led to decreased vascular density and lumen formation. In both cases, lack of epithelial integrin β1 was associated with a complete absence of vasculature in the pituitary gland at birth. Within pituitary epithelial cells, integrin β1 directs a large transcriptional program that includes components of the extracellular matrix and associated signaling factors that are linked to the observed non-cell-autonomous effects on angiogenesis. We conclude that epithelial integrin β1 functions as a critical and canonical regulator of developmental angiogenesis in the pituitary gland, thus providing insight into the long-standing systems biology conundrum of how vascular invasion is coordinated with tissue development.angiogenesis | integrin β1 | pituitary gland | mice

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“…Beyond angiogenic growth factors, there is evidence that integrins are implicated in angiogenesis [23]. Specifically, endothelialrestricted deficiency of b1-integrins and of the a5-integrin subunit of the b1-integrins impairs in vivo angiogenesis [4,31,49,50,52]. However, the effects of increased integrindependent EC adhesion on angiogenesis are still elusive.…”

Section: Introductionmentioning

confidence: 99%

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

et al. 2014

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b1-Integrins are essential for angiogenesis. The mechanisms regulating integrin function in endothelial cells (EC) and their contribution to angiogenesis remain elusive. Brag2 is a guanine nucleotide exchange factor for the small Arf-GTPases Arf5 and Arf6. The role of Brag2 in EC and angiogenesis and the underlying molecular mechanisms remain unclear. siRNA-mediated Brag2-silencing reduced EC angiogenic sprouting and migration. Brag2-siRNA transfection differentially affected a5b1-and aVb3-integrin function: specifically, Brag2-silencing increased focal/fibrillar adhesions and adhesion on b1-integrin ligands (fibronectin and collagen), while reducing the adhesion on the aVb3-integrin ligand, vitronectin. Consistent with these results, Brag2-silencing enhanced surface expression of a5b1-integrin, while reducing surface expression of aVb3-integrin. Mechanistically, Brag2-mediated aVb3-integrin-recycling and b1-integrin endocytosis and specifically of the active/matrix-bound a5b1-integrin present in fibrillar/focal adhesions (FA), suggesting that Brag2 contributes to the disassembly of FA via b1-integrin endocytosis. Arf5 and Arf6 are promoting downstream of Brag2 angiogenic sprouting, b1-integrin endocytosis and the regulation of FA. In vivo silencing of the Brag2-orthologues in zebrafish embryos using morpholinos perturbed vascular development. Furthermore, in vivo intravitreal injection of plasmids containing Brag2-shRNA reduced pathological ischemia-induced retinal and choroidal neovascularization. These data reveal that Brag2 is essential for developmental and pathological angiogenesis by promoting EC sprouting through regulation of adhesion by mediating b1-integrin internalization and link for the first time the process of b1-integrin endocytosis with angiogenesis.

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Integrin-dependent and -independent functions of astrocytic fibronectin in retinal angiogenesis

Cited by 128 publications

References 47 publications

Integrin β1 controls VE-cadherin localization and blood vessel stability

Integrin β1 controls VE-cadherin localization and blood vessel stability

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

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