Endothelial α5 and αv integrins cooperate in remodeling of the vasculature during development

Flier, Arjan van der; Badu-Nkansah, Kwabena; Whittaker, Charles A.; Crowley, Denise; Bronson, Roderick T.; Lacy‐Hulbert, Adam; Hynes, Richard O.

doi:10.1242/dev.049551

Cited by 156 publications

(176 citation statements)

References 71 publications

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“…To define which receptors mediate HUAEC binding to the endothelial laminins, functional‐blocking antibodies to integrins β1 (P5D2), α3 (P1B5), α6 (GoH3), α5 (P1D6) and αv (LM609) either alone or in combination were included in the adhesion assays. Fibronectin was employed as a positive control, where binding is known to be integrin α5β1‐mediated (van der Flier et al , 2010). Laminin 111 was used as a non‐endothelial laminin isoform.…”

Section: Resultsmentioning

confidence: 99%

Endothelial basement membrane laminin 511 is essential for shear stress response

Russo¹,

Luik²,

Yousif³

et al. 2016

The EMBO Journal

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Shear detection and mechanotransduction by arterial endothelium requires junctional complexes containing PECAM‐1 and VE‐cadherin, as well as firm anchorage to the underlying basement membrane. While considerable information is available for junctional complexes in these processes, gained largely from in vitro studies, little is known about the contribution of the endothelial basement membrane. Using resistance artery explants, we show that the integral endothelial basement membrane component, laminin 511 (laminin α5), is central to shear detection and mechanotransduction and its elimination at this site results in ablation of dilation in response to increased shear stress. Loss of endothelial laminin 511 correlates with reduced cortical stiffness of arterial endothelium in vivo, smaller integrin β1‐positive/vinculin‐positive focal adhesions, and reduced junctional association of actin–myosin II. In vitro assays reveal that β1 integrin‐mediated interaction with laminin 511 results in high strengths of adhesion, which promotes p120 catenin association with VE‐cadherin, stabilizing it at cell junctions and increasing cell–cell adhesion strength. This highlights the importance of endothelial laminin 511 in shear response in the physiologically relevant context of resistance arteries.

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Section: Resultsmentioning

confidence: 99%

Endothelial basement membrane laminin 511 is essential for shear stress response

Russo¹,

Luik²,

Yousif³

et al. 2016

The EMBO Journal

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“…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 . Inactivation of Itga3 or Itga4, the genes encoding the a3-and a4-subunits, respectively, in ECs was also compatible with mutant survival 46,47 .…”

Section: Discussionmentioning

confidence: 93%

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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“…Ultrastructurally, a thickened basement membrane associated with Reichart's membrane is apparent in Abi1 −/− mice, suggestive of defects in integrin activation (Fig. 2 H-J) (29). Comparison of the phenotypes of Abi1 −/− mice on the C57BL/6 and CD1 strains suggest that defects arising in chorionic trophoblast cells may underlie the aberrant placentation observed in both of these strains.…”

Section: Placental Abnormalities Are Associated With Chorionic Defectmentioning

confidence: 95%

Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the α4 integrin

Ring

Ginsberg

Haling

et al. 2010

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

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Dynamic signals linking the actin cytoskeleton and cell adhesion receptors are essential for morphogenesis during development and normal tissue homeostasis. Abi1 is a central regulator of actin polymerization through interactions with multiple protein complexes. However, the in vivo role of Abi1 remains to be defined. The α4 integrin adhesion receptor is associated with enhanced protrusive activity and regulation of directional cell migration. Among integrin subunits, α4 exhibits unique properties in that it predominantly accumulates at the leading edge of migrating cells; however, the pathways that link the actin-regulatory machinery to α4 at the leading edge have remained elusive. We generated Abi1 KO mice and found that loss of Abi1 phenocopies KO of α4. Mice lacking Abi1 or α4 exhibit midgestational lethality with abnormalities in placental and cardiovascular development. Notably, purified Abi1 protein binds directly to the α4 cytoplasmic tail and endogenous Abi1 colocalizes with phosphorylated α4 at the leading edge of spreading cells. Moreover, Abi1-deficient cells expressing α4 have impaired cell spreading, which is rescued by WT Abi1 but not an Abi1 mutant lacking the α4-binding site. These data reveal a direct link between the α4 integrin and actin polymerization and uncover a role for Abi1 in the regulation of morphogenesis in vivo. The Abi1–α4 interaction establishes a mechanistic paradigm for signaling between adhesion events and enhanced actin polymerization at the earliest stages of protrusion.

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Endothelial α5 and αv integrins cooperate in remodeling of the vasculature during development

Cited by 156 publications

References 71 publications

Endothelial basement membrane laminin 511 is essential for shear stress response

Endothelial basement membrane laminin 511 is essential for shear stress response

Integrin β1 controls VE-cadherin localization and blood vessel stability

Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the α4 integrin

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