The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR2

Gaengel, Konstantin; Niaudet, Colin; Hagikura, Kazuhiro; Laviña, Bàrbara; Muhl, Lars; Hofmann, Jennifer; Ebarasi, Lwaki; Nyström, Staffan; Rymo, Simin; Chen, Long Long; Pang, Mei-Fong; Jin, Yi; Raschperger, Elisabeth; Roswall, Pernilla; Schulte, Dörte; Benedito, Rui; Larsson, Jimmy; Hellström, Mats; Fuxe, Jonas; Uhlén, Per; Adams, Ralf H.; Jakobsson, Lars; Majumdar, Årindam; Vestweber, Dietmar; Uv, Anne; Betsholtz, Christer

doi:10.1016/j.devcel.2012.11.007

Cited by 48 publications

(101 citation statements)

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“…Previous work has established that VE-cadherin, a main component of endothelial adherens junctions, is essential for angiogenesis and, in particular, the suppression of EC sprouting and proliferation 24,25 . We found that VE-cadherin distribution was substantially altered in Itgb1 iECKO retinal vessels (Fig.…”

Section: Inducible Inactivation Of Itgb1 In the Postnatal Endotheliummentioning

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: Inducible Inactivation Of Itgb1 In the Postnatal Endotheliummentioning

confidence: 99%

Integrin β1 controls VE-cadherin localization and blood vessel stability

et al. 2015

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“…Under these conditions, HLMVECs did not migrate against the flow direction over the course of 20 h, with many of the cells showing no directional preference (figure 4a,c; electronic supplementary material, figure S4). We next performed the same experiment, but supplemented media prepared with charcoal-stripped FBS and 100 nM of S1P, a physiologically relevant concentration [24,26,38] ( figure 4b,c). Under this condition, HLMVECs migrated against the flow direction with near identical radial migration distances and persistence to those of control, untreated, HLMVECs (figure 4d and electronic supplementary material,…”

Section: S1pr1 Is Required For Persistent Directional Migration In Rmentioning

confidence: 99%

“…In this model, S1PR1 may not be mechanically activated by flow, but is required to activate downstream signalling involved in flow-mediated collective migration. Given the known requirement of S1PR1 activity in proper VE-Cadherin localization in the developing microvasculature [24], it is possible that signalling via S1PR1 influences the assembly of the flow sensing complex consisting of PECAM, VE-Cadherin and VEGFR2/3 [10,17,21,55], and hence indirectly regulates flow sensing via this pathway.…”

Section: Cs-l15mentioning

confidence: 99%

“…Interface 13: 20160823 S1PR1 is also required for the HLMVEC migration against the flow direction (figure 2). Addition of 1 mM W146, a specific and potent S1PR1 inhibitor [24], abolished net inward migration in response to impinging flow (figure 2a,b). S1PR1 inhibition with W146 (1 mM) likewise blocked net inward migration at flow conditions which resulted in peak WSS of 72 dynes cm 22 , demonstrating the robustness of the result (electronic supplementary material, figure S6a).…”

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confidence: 95%

“…mice die in utero between E13.5 and E14.5 due to defects in vascular stabilization [23][24][25][26][27]. How S1PR1 contributes to vessel stabilization is incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

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Sphingosine 1-phosphate receptor 1 regulates the directional migration of lymphatic endothelial cells in response to fluid shear stress

Surya

Michalaki

Huang

et al. 2016

J. R. Soc. Interface.

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The endothelial cells that line blood and lymphatic vessels undergo complex, collective migration and rearrangement processes during embryonic development, and are known to be exquisitely responsive to fluid flow. At present, the molecular mechanisms by which endothelial cells sense fluid flow remain incompletely understood. Here, we report that both the G-protein-coupled receptor sphingosine 1-phosphate receptor 1 (S1PR1) and its ligand sphingosine 1-phosphate (S1P) are required for collective upstream migration of human lymphatic microvascular endothelial cells in an in vitro setting. These findings are consistent with a model in which signalling via S1P and S1PR1 are integral components in the response of lymphatic endothelial cells to the stimulus provided by fluid flow.

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The E3 ubiquitin ligase MARCH3 controls the endothelial barrier

et al. 2016

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Cell-cell contacts coordinate the endothelial barrier function in response to external cues. To identify new mediators involved in cytokine-promoted endothelial permeability, we screened a siRNA library targeting E3 ubiquitin ligases. Here, we report that silencing of the late endosome/lysosomal membrane-associated RING-CH-3 (MARCH3) enzyme protects the endothelial barrier. Furthermore, transcriptome analysis unmasked the upregulation of the tight junction-encoding gene occludin (OCLN) in MARCH3-depleted cells. Indeed, MARCH3 silencing results in the strengthening of cell-cell contacts, as evidenced by the accumulation of junctional proteins. From a molecular standpoint, the FoxO1 forkhead transcription repressor was inactivated in the absence of MARCH3. This provides a possible molecular link between MARCH3 and the signaling pathway involved in regulating the expression of junctional proteins and barrier integrity.

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The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR2

Abstract: In the originally published version of this article, author Bà rbara Laviñ a was mistakenly listed as ''Bà rbara Laviñ a Siemsen.'' This error has now been corrected in the article online. We apologize for the error and any inconvenience that may have resulted.

Cited by 48 publications

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Integrin β1 controls VE-cadherin localization and blood vessel stability

Integrin β1 controls VE-cadherin localization and blood vessel stability

Sphingosine 1-phosphate receptor 1 regulates the directional migration of lymphatic endothelial cells in response to fluid shear stress

The E3 ubiquitin ligase MARCH3 controls the endothelial barrier

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