Impaired Hedgehog signalling-induced endothelial dysfunction is sufficient to induce neuropathy: implication in diabetes

Chapouly, Candice; Yao, Qinyu; Vandierdonck, Soizic; Larrieu-Lahargue, Frédéric; Mariani, John N.; Gadeau, Alain‐Pierre; Renault, Marie-Ange

doi:10.1093/cvr/cvv263

Cited by 57 publications

(49 citation statements)

References 50 publications

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“…To confirm that endothelial Dhh and ectopic N-Shh induce opposite effects on ECs, we compared their effect on endothelial barrier integrity. Consistent, with previous investigations 17,27 , expression of both Cdh5 and Cldn5 was significantly diminished at the BBB of Dhh ECKO mice compared to littermate controls (Figure 2A-D). This was associated with fibrinogen and albumin extravasation (Figure 2A-B, E-F) demonstrating abnormal BBB permeability.…”

Section: Endothelial Dhh Promotes Bbb Integrity While Ectopic Adminissupporting

confidence: 92%

Endothelial cell response to Hedgehog ligands depends on their processing

Hollier

Chapouly

Diop

et al. 2020

Preprint

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Rationale:The therapeutic potential of Hedgehog (Hh) signaling agonists for vascular diseases is of growing interest. However, molecular and cellular mechanisms underlying the role of the Hh signaling in vascular biology remain poorly understood. Objective: The purpose of the present paper is to clarify some conflicting literature data. Findings: With this goal we have demonstrated that, unexpectedly, ectopically administered N-terminal Sonic Hedgehog (N-Shh) and endogenous endothelial-derived Desert Hedgehog (Dhh) induce opposite effects in endothelial cells. (ECs). Notably, endothelial Dhh acts under its full-length soluble form (FL-Dhh) and activates Smoothened in ECs, while N-Shh inhibits it. At molecular level, N-Shh prevents FL-Dhh binding to Patched-1 demonstrating that N-Shh acts as competitive antagonist to FL-Dhh. Besides, we found that even though FL-Hh ligands and N-Hh ligands all bind Patched-1, they induce specific Patched-1 localization. Finally, we confirmed that in a pathophysiological setting i.e. brain inflammation, astrocyte-derived N-Shh act as a FL-Dhh antagonist. Conclusion: The present study highlights for the first time that FL-Dhh and N-Hh ligands have antagonistic properties especially in ECs, and demonstrates that Hh ligands or forms of Hh ligands cannot be used instead of another for therapeutic purposes.

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Section: Endothelial Dhh Promotes Bbb Integrity While Ectopic Adminissupporting

confidence: 92%

Endothelial cell response to Hedgehog ligands depends on their processing

Hollier

Chapouly

Diop

et al. 2020

Preprint

Self Cite

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“…Nevertheless, many rodent models of diabetes exhibit indicators of Schwann cell dysfunction, including reduced expression of myelin-associated proteins 47 and Schwann cell-derived trophic factors, such as CNTF 19 and desert hedgehog 20,48 . These perturbations have the potential to affect both neuronal 49 and vascular 48 function, and changes in CNTF expression are prevented by aldose reductase inhibition 50 . In addition, studies in cultured Schwann cells have suggested that increased flux through the polyol pathway drives Schwann cells towards an immature phenotype 51 .…”

Section: Polyneuropathy Mononeuropathiesmentioning

confidence: 99%

Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

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The incidence of diabetes mellitus has increased dramatically over the past two to three decades. According to the International Diabetes Federation Diabetes Atlas, 415 million people worldwide had diabetes in 2015, and this number is expected to grow by 5% annually, predominantly as a result of increasing prevalence of type 2 diabetes. Furthermore, an estimated 100 million Europeans and 80 million Americans have impaired glucose tolerance or prediabetes. Few people die from acute diabetes in countries with comprehensive health care systems, but the disease is inflicting a huge medical, social and economic burden on society owing to the need for lifelong treatment of its systemic consequences and the insidious development of multi-organ damage.Peripheral neuropathy (BOXES 1,2) is a common but often neglected complication of long-term diabetes, and the lack of treatment options reflects an incomplete understanding of the pathogenic mechanisms. Hyperglycaemia is generally accepted as the primary pathogenic insult in type 1 and type 2 diabetic neuropathy, although roles are emerging for other factors, such as impaired insulin signalling, hypertension and dyslipidaemia (particularly for type 2 diabetes), which might precede overt hyperglycaemia 1 . Many preclinical studies, and occasional clinical studies, have indicated that diabetic neuropathy -like diabetic nephropathy and retinopathy -results from microvascular disease, with a focus on axonal degeneration as a consequence of ischaemia and/or hypoxia. This mechanism, however, is likely to be only one aspect of a more complex pathogenesis.The earliest descriptions of pathology in diabetic neuropathy indicated that Schwannopathy accompanied axonal degeneration. The majority of clinical and basic research in diabetic neuropathy since then has focused on the effects on neurons. However, accumulating data from research into the development and regeneration of the PNS has identified Schwann cells as equally indispensable components that maintain neuronal structure and function, nourish axons, and promote survival and growth upon injury. The early reports from 1979 that demonstrated morphological changes in Schwann cells in human diabetic neuropathy 2 are now supported by an increased awareness of molecular alterations in Schwann cells during diabetes 3 . Schwann cells express a wide range of receptors and, when they sense insults or danger signals, they upregulate synthesis and secretion of factors that stimulate neuroprotection, regrowth and remyelination, or factors that aggravate disease phenotypes 4 . The most recent studies have demonstrated that Schwann cells regulate many aspects of axonal function, so that disruption of their metabolism by diabetes results in the accumulation of neurotoxic intermediates and compromises production of neuronal support factors, contributing to axonal degeneration, endothelial dysfunction and diabetic neuropathy. Abstract | The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annu...

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“…This resulted in increased local vascular permeability, local immunocytes infiltration, and neuropathic-like behavior development (mechanical allodynia) in CCI-injured rats. 4 , 5 , 9 Nevertheless, neither the preemptive inhibition of TLR4 signaling nor the preemptive activation of Hedgehog signaling in healthy nerves could prevent the molecular, vascular, and behavioral changes resulting from CCI, suggesting the possibility of other players in this pathological context.…”

Section: Introductionmentioning

confidence: 99%

Could an endoneurial endothelial crosstalk between Wnt/β-catenin and Sonic Hedgehog pathways underlie the early disruption of the infraorbital blood–nerve barrier following chronic constriction injury?

et al. 2017

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BackgroundBlood–nerve barrier disruption is pivotal in the development of neuroinflammation, peripheral sensitization, and neuropathic pain after peripheral nerve injury. Activation of toll-like receptor 4 and inactivation of Sonic Hedgehog signaling pathways within the endoneurial endothelial cells are key events, resulting in the infiltration of harmful molecules and immunocytes within the nerve parenchyma. However, we showed in a previous study that preemptive inactivation of toll-like receptor 4 signaling or sustained activation of Sonic Hedgehog signaling did not prevent the local alterations observed following peripheral nerve injury, suggesting the implication of another signaling pathway.MethodsUsing a classical neuropathic pain model, the infraorbital nerve chronic constriction injury (IoN-CCI), we investigated the role of the Wnt/β-catenin pathway in chronic constriction injury-mediated blood–nerve barrier disruption and in its interactions with the toll-like receptor 4 and Sonic Hedgehog pathways. In the IoN-CCI model versus control, mRNA expression levels and/or immunochemical detection of major Wnt/Sonic Hedgehog pathway (Frizzled-7, vascular endothelial-cadherin, Patched-1 and Gli-1) and/or tight junction proteins (Claudin-1, Claudin-5, and Occludin) readouts were assessed. Vascular permeability was assessed by sodium fluorescein extravasation.ResultsIoN-CCI induced early alterations in the vascular endothelial-cadherin/β-catenin/Frizzled-7 complex, shown to participate in local blood–nerve barrier disruption via a β-catenin-dependent tight junction protein downregulation. Wnt pathway also mediated a crosstalk between toll-like receptor 4 and Sonic Hedgehog signaling within endoneurial endothelial cells. Nevertheless, preemptive inhibition of Wnt/β-catenin signaling before IoN-CCI could not prevent the downregulation of key Sonic Hedgehog pathway readouts or the disruption of the infraorbital blood–nerve barrier, suggesting that Sonic Hedgehog pathway inhibition observed following IoN-CCI is an independent event responsible for blood–nerve barrier disruption.ConclusionA crosstalk between Wnt/β-catenin- and Sonic Hedgehog-mediated signaling pathways within endoneurial endothelial cells could mediate the chronic disruption of the blood–nerve barrier following IoN-CCI, resulting in increased irreversible endoneurial vascular permeability and neuropathic pain development.

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Impaired Hedgehog signalling-induced endothelial dysfunction is sufficient to induce neuropathy: implication in diabetes

Abstract: The present work demonstrates the critical role of Dhh in maintaining blood nerve barrier integrity and demonstrates for the first time that endothelial dysfunction is sufficient to induce neuropathy.

Cited by 57 publications

References 50 publications

Endothelial cell response to Hedgehog ligands depends on their processing

Endothelial cell response to Hedgehog ligands depends on their processing

Schwann cell interactions with axons and microvessels in diabetic neuropathy

Could an endoneurial endothelial crosstalk between Wnt/β-catenin and Sonic Hedgehog pathways underlie the early disruption of the infraorbital blood–nerve barrier following chronic constriction injury?

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