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Environmental and intrinsic modulations of venous differentiation

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Abstract

Endothelial cells in veins differ in morphology, function and gene expression from those in arteries and lymphatics. Understanding how venous and arterial identities are induced during development is required to understand how arterio-venous malformations occur, and to improve the outcome of vein grafts in surgery by promoting arterialization of veins. To identify factors that promote venous endothelial cell fate in vivo, we isolated veins from quail embryos, at different developmental stages, that were grafted into the coelom of chick embryos. Endothelial cells migrated out from the grafted vein and their colonization of host veins and/or arteries was quantified. We show that venous fate is promoted by sympathetic vessel innervation at embryonic day 11. Removal of sympathetic innervation decreased vein colonization, while norepinephrine enhanced venous colonization. BMP treatment or inhibition of ERK enhanced venous fate, revealing environmental neurotransmitter and BMP signaling and intrinsic ERK inhibition as actors in venous fate acquisition. We also identify the BMP antagonist Noggin as a potent mediator of venous arterialization.

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All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Abbreviations

AC:

Adenylate cyclase

ADR:

Adrenoreceptors

ALK:

Activin receptor-like kinase

AVM:

Arterio-venous malformations

BMP:

Bone morphogenetic protein

CAM:

Chorioallantois membrane

CX40:

Connexin 40

DM:

Dorsomorphin

DMH-1:

Dorsomorphin-homolog-1

EC:

Endothelial cells

ERK:

Extracellular signal-regulated kinases

FCS:

Fetal calf serum

HDAC1:

Histone deacetylase 1

HHT:

Hereditary hemorrhagic telangiectasia

6HDOPA:

6-Hydroxydopamine

JV:

Jugular vein

NE:

Norepinephrine

PCV:

Posterior cardinal vein

PE:

Phenylephrine

PKA:

Protein kinase A

QH1:

Quail hemopoietic-1

SOV:

Sodium orthovanadate

VEGF:

Vascular endothelial growth factor

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Funding

This work was supported by the Institut national de la santé et de la recherche médicale (Inserm) and the European Research Council grant agreement No. 834161.

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Authors and Affiliations

  1. Université de Paris Cité, Inserm, PARCC, 75015, Paris, France

    Laurence Pibouin-Fragner, Anne Eichmann & Luc Pardanaud

  2. Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

    Anne Eichmann

  3. Department of Molecular and Cellular Physiology, Yale University School of Medicine, New Haven, CT, USA

    Anne Eichmann

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  1. Laurence Pibouin-Fragner
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  3. Luc Pardanaud
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Correspondence to Anne Eichmann or Luc Pardanaud.

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Supplementary Information

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18_2022_4470_MOESM1_ESM.psd

Supplementary file1 Figure S1 Transverse sections at the truncal level of an E4 chick host, 2 days after the graft of a quail E8 JV. Triple staining using the QH1 antibody (blue), an anti-CX40 antibody that recognizes arteries (green) and the Sambucus nigra lectin that stains all avian vessels (red). The CX40 + /Sambucus + aortae (Ao) appear orange while cardinal vein (CV) and umbilical vein (UV) are only Sambucus + . A) The arrow indicates a quail EC (blue-green) that reaches the aortic endothelium. The arrowhead shows a QH1 + EC counted as an arterial EC because a ventral aortic branch is present close to this cell on a consecutive section. B) The arrow points to a grafted quail QH1 + /Sambucus + EC (purple) participating to the UV endothelium. Arrowheads indicate QH1 + ECs close to chick veins and counted as venous ECs because a venous branch is present close to these cells on a consecutive section. Blue QH1 + cells that were not counted are present near the graft (G). M: mesonephros. (PSD 26261 kb)

18_2022_4470_MOESM2_ESM.psd

Supplementary file2 Figure S2 Number of emigrating QH1 + ECs from untreated E8 JVs and E8 JV treated by PE and BHT933, each dot corresponds to one JV sample. By comparison with E8 JVs, Mann–Whitney or Unpaired 2-tailed nonparametric t tests. Error bars: SEM, n: number of grafts. (PSD 1495 kb)

18_2022_4470_MOESM3_ESM.psd

Supplementary file3 Figure S3 Quantification of BMP effects (high doses) on host venous colonization by QH1 + ECs from E8 JVs, each dot corresponds to one JV sample.*P < 0.05, by comparison with E8 JVs, Mann–Whitney or Unpaired 2-tailed nonparametric t tests. Error bars: SEM, n: number of grafts. The blue numbers correspond to the total number of cells counted in each condition. (PSD 2610 kb)

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Pibouin-Fragner, L., Eichmann, A. & Pardanaud, L. Environmental and intrinsic modulations of venous differentiation. Cell. Mol. Life Sci. 79, 491 (2022). https://doi.org/10.1007/s00018-022-04470-4

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