Netrin-1 controls sympathetic arterial innervation

Brunet, Isabelle; Gordon, Emma; Han, Joungho; Cristofaro, Brunella; Broquères-You, Dong; Li, Chun; Bouvrée, Karine; Zhang, Jiasheng; Toro, R.; Mathivet, Thomas; Larrivée, Bruno; Jagu, Julia; Pibouin-Fragner, Laurence; Pardanaud, Luc; Machado, Maria J. C.; Kennedy, Timothy E.; Zhuang, Zhen W.; Simons, Michael; Lévy, Bernard; Tessier‐Lavigne, Marc; Grenz, Almut; Eltzschig, Holger K.; Eichmann, Anne

doi:10.1172/jci75181

Cited by 84 publications

(87 citation statements)

References 60 publications

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“…The glial-derived neurotrophic factor (GDNF) family member artemin, and the neurotrophins Nerve growth factor (NGF) and neurotrophin-3 (NT-3) are expressed in embryonic arterial SMCs, and inactivation of the genes encoding these molecules in mice leads to defects in sympathetic axon growth and extension along the arterial vasculature 39, 40 . Postnatal arterial SMCs acquire the expression of the axon guidance molecule netrin-1, which is required for innervation of arterial SMCs by sympathetic neurons 41 .…”

Section: Arteriogenesis In Developmentmentioning

confidence: 99%

Molecular Controls of Arterial Morphogenesis

Simons

Eichmann

2015

Circulation Research

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114

119

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Formation of arterial vasculature, here termed arteriogenesis, is a central process in embryonic vascular development as well as in adult tissues. While the process of capillary formation, angiogenesis, is relatively well understood, much remains to be learned about arteriogenesis. Recent discoveries point to the key role played by vascular endothelial growth factor receptor 2 (VEGFR2) in control of this process and to newly identified control circuits that dramatically influence its activity. The latter can present particularly attractive targets for a new class of therapeutic agents capable of activation of this signaling cascade in a ligand-independent manner, thereby promoting arteriogenesis in diseased tissues.

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Section: Arteriogenesis In Developmentmentioning

confidence: 99%

Molecular Controls of Arterial Morphogenesis

Simons

Eichmann

2015

Circulation Research

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114

119

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“…22 The newly specified arteries recruit smooth muscle cells that induce noradrenergic differentiation of sympathetic progenitors 58 and promote extension and growth of sympathetic nerve fibers along the arteries and eventually arterial innervation. 59,60 Innervation occurs during late gestation in avian embryos, which are fully motile at birth, whereas it occurs postnatally in mice, 60 which remain immature and acquire full motility only about postnatal day 10. Catecholamine release in turn contributes to maintenance of arterial fate, revealing a positive feedback loop between nerve-induced arterial function and arterial morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

Sympathetic Innervation Promotes Arterial Fate by Enhancing Endothelial ERK Activity

Pardanaud

Pibouin-Fragner

Dubrac

et al. 2016

Circulation Research

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Rationale: Arterial endothelial cells are morphologically, functionally, and molecularly distinct from those found in veins and lymphatic vessels. How arterial fate is acquired during development and maintained in adult vessels is incompletely understood. Objective:We set out to identify factors that promote arterial endothelial cell fate in vivo. Methods and Results:We developed a functional assay, allowing us to monitor and manipulate arterial fate in vivo, using arteries isolated from quails that are grafted into the coelom of chick embryos. Endothelial cells migrate out from the grafted artery, and their colonization of host arteries and veins is quantified. Here we show that sympathetic innervation promotes arterial endothelial cell fate in vivo. Removal of sympathetic nerves decreases arterial fate and leads to colonization of veins, whereas exposure to sympathetic nerves or norepinephrine imposes arterial fate. Mechanistically, sympathetic nerves increase endothelial ERK (extracellular signal-regulated kinase) activity via adrenergic α1 and α2 receptors. Conclusions:

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“…18 Additionally, a recent study has shown that netrin-1 and its receptor, DCC, control sympathetic arterial innervation and play an important role in the regulation of the blood flow to peripheral organs. 19 Moreover, netrin-1 binding to specific receptors like DCC has been shown to activate multiple pathways including MAPKs, PKC, src, Rac and Rho kinase, and focal adhesion kinase 20–22 , which all have been previously reported to be associated with HTN and BP regulation. 23–25 Furthermore, a recent study has demonstrated that netrin-1 activates PRKC alpha , and FAK/Fyn, which are important for the activation of the ERK, JNK and NF-kB.…”

Section: Discussionmentioning

confidence: 99%

A Genetic Response Score for Hydrochlorothiazide Use

et al. 2016

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Hydrochlorothiazide (HCTZ) is among the most commonly prescribed antihypertensives, yet <50% of HCTZ treated patients achieve blood pressure (BP) control. Herein, we integrated metabolomic and genomic profiles of HCTZ treated patients to identify novel genetic markers associated with HCTZ BP response. The primary analysis included 228 white hypertensives treated with HCTZ from the Pharmacogenomic Evaluation of Antihypertensive Response study. Genome-wide analysis was conducted using Illumina Omni 1M-Quad Chip, and untargeted metabolomics was performed on baseline fasting plasma samples using a gas chromatography-time-of-flight mass spectrometry platform. We found thirteen metabolites significantly associated with HCTZ systolic BP (SBP) and diastolic BP (DBP) responses (FDR<0.05). Additionally, integrating genomics and metabolomics data revealed three polymorphisms (rs2727563 PRKAG2, rs12604940 DCC, and rs13262930 EPHX2) along with arachidonic acid, converging in the netrin signaling pathway (p=1×10−5), as potential markers significantly influencing HCTZ BP response. We successfully replicated the three genetic signals in 212 white hypertensives treated with HCTZ, and created a response score by summing their BP lowering alleles. We found patients carrying one response allele had a significantly lowest response than carriers of six alleles (ΔSBP/ΔDBP: −1.5/1.2 vs −16.3/−10.4 mmHg, respectively, SBP-score p=1×10−8 and DBP-score p=3×10−9). This score explained 11.3% and 11.9% of the variability in HCTZ SBP and DBP responses, respectively, and was further validated in another independent study of 196 whites treated with HCTZ (DBP-score p=0.03, SBP-score p=0.07). This study suggests that PRKAG2, DCC and EPHX2 might be important determinants of HCTZ BP response.

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Netrin-1 controls sympathetic arterial innervation

Cited by 84 publications

References 60 publications

Molecular Controls of Arterial Morphogenesis

Molecular Controls of Arterial Morphogenesis

Sympathetic Innervation Promotes Arterial Fate by Enhancing Endothelial ERK Activity

A Genetic Response Score for Hydrochlorothiazide Use

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