Publications by authors named "Bérengère Fromy"

38 Publications

[Functional integrity of aging skin, from cutaneous biology to anti-aging strategies].

Med Sci (Paris) 2020 Dec 9;36(12):1155-1162. Epub 2020 Dec 9.

Équipe Intégrité fonctionnelle du tissu cutané (SKIN). Laboratoire de biologie tissulaire et d'ingénierie thérapeutique (LBTI), CNRS UMR5305, Université Lyon I, 7 passage du Vercors, 69367 Lyon Cedex 07, France.

The skin is a sentinel organ making easily visible the passing of time. Chronological and environmental aging weakens skin structure and functions. The skin barrier, the elastic and mechanical properties of the cutaneous tissue as well as its vascular reactivity are impacted by aging. The barrier dysfunction in aged skin is caused by defects in epidermal keratinocytes renewal and differentiation notably linked to abnormal expression of microRNAs regulating cell death and autophagy. An abnormal balance between synthesis and degradation of matrix proteins modifies the mechanical properties of the dermis in aged skin. Finally, a reduction of the vascular reactivity linked to endothelial dysfunctions is observed in elderly people. These biological processes can be targeted by therapeutic approaches either topical or systemic, especially using anti-oxydants or senolytics. These anti-aging strategies might contribute to restore, at least in part, the functional integrity of aged skin.
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http://dx.doi.org/10.1051/medsci/2020223DOI Listing
December 2020

Advanced Characterization of Imiquimod-Induced Psoriasis-Like Mouse Model.

Pharmaceutics 2020 Aug 20;12(9). Epub 2020 Aug 20.

UMR 5305: Laboratoire de Biologie Tissulaire et d'Ingénierie Thérapeutique, CNRS/Université Claude Bernard Lyon 1, Institut de Biologie et Chimie des Protéines, 7 passage du Vercors, 69367 Lyon CEDEX 07, France.

Many autoimmune disorders such as psoriasis lead to the alteration of skin components which generally manifests as unwanted topical symptoms. One of the most widely approved psoriasis-like animal models is the imiquimod (IMQ)-induced mouse model. This representation mimics various aspects of the complex cutaneous pathology and could be appropriate for testing topical treatment options. We perform a thorough characterization of this model by assessing some parameters that are not fully described in the literature, namely a precise description of skin disruption. It was evaluated by transepidermal water loss measurements and analyses of epidermis swelling as a consequence of keratinocyte hyperproliferation. The extent of neo-angiogenesis and hypervascularity in dermis were highlighted by immunostaining. Moreover, we investigated systemic inflammation through cytokines levels, spleen swelling and germinal centers appearance in draining lymph nodes. The severity of all parameters was correlated to IMQ concentration in skin samples. This study outlines new parameters of interest useful to assess this model. We highlight the skin barrier disruption and report a systemic inflammatory reaction occurring at distance both in spleen and lymph nodes. These newly identified biological endpoints could be exploited to investigate the efficacy of therapeutic candidates for psoriasis and more extensively for several other skin inflammatory diseases.
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http://dx.doi.org/10.3390/pharmaceutics12090789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558091PMC
August 2020

Dietary Supplementation with Silicon-Enriched Spirulina Improves Arterial Remodeling and Function in Hypertensive Rats.

Nutrients 2019 Oct 25;11(11). Epub 2019 Oct 25.

PhyMedExp, Université de Montpellier, INSERM U1046, CNRS UMR9214, 34295 Montpellier, France.

Vascular aging is characterized by increase in arterial stiffness and remodeling of the arterial wall with a loss of elastic properties. Silicon is an essential trace element highly present in arteries. It is involved in the constitution and stabilization of elastin fibers. The nutritional supply and bioavailability of silicon are often inadequate. Spirulina (Sp), micro algae have recognized nutritional properties and are able to incorporate minerals in a bioavailable form. We evaluated the effects of nutritional supplementation with silicon-enriched spirulina (SpSi) on arterial system structure and function in hypertension. Experiments were performed on hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats supplemented with SpSi or Sp over a period of three months. Arterial pressure, vascular function and morphometric parameters of thoracic aorta were analyzed. SpSi supplementation lowered arterial pressure in SHR and minimized morphometric alterations induced by hypertension. Aortic wall thickness and elastic fibers fragmentation were partially reversed. Collagen and elastin levels were increased in association with extracellular matrix degradation decrease. Vascular reactivity was improved with better contractile and vasorelaxant responses to various agonists. No changes were observed in SHR supplemented with Sp. The beneficial effects of SpSi supplementation evidenced here, may be attributable to Si enrichment and offer interesting opportunities to prevent cardiovascular risks.
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http://dx.doi.org/10.3390/nu11112574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893466PMC
October 2019

Substrate softness promotes terminal differentiation of human keratinocytes without altering their ability to proliferate back into a rigid environment.

Arch Dermatol Res 2019 Dec 7;311(10):741-751. Epub 2019 Aug 7.

CNRS/UCBL, University Lyon 1, UMR 5305, Laboratory of Tissue Biology and Therapeutic Engineering, LBTI, IBCP, 7, passage du Vercors, 69367, Lyon cedex 7, France.

Substrate stiffness is a key regulator of cell behavior. To investigate how mechanical properties of cell microenvironment affect the human keratinocyte, primary cells were seeded on polyacrylamide hydrogels of different compliances (soft: 4 kPa, medium: 14 kPa, rigid: 45 kPa) in comparison with glass coverslip (> GPa). Keratinocyte spreading and proliferation were strongly decreased on the softest hydrogel, while no significant difference was observed between medium, rigid hydrogels and glass coverslip, and cells' viability was comparable in all conditions after 72 h. We then performed a RNA-seq to compare the transcriptomes from keratinocytes cultured for 72 h on the softest hydrogel or on coverslips. The cells on the soft hydrogel showed a strong increase in the expression of late differentiation marker genes from the epidermal differentiation complex (1q21) and the antioxidant machinery. In parallel, these cells displayed a significant loss of expression of the matrix receptors (integrin α6 and β1) and the EGF receptor. However, when these cells were replated on a plastic culture plate (> GPa), they were able to re-engage the proliferation machinery with a strong colony-formation efficiency. Overall, using low-calcium differentiation monolayers at confluence, the lesser the rigidity, the stronger the markers of late differentiation are expressed, while the inverse is observed regarding the markers of early differentiation. In conclusion, below a certain rigidity, human keratinocytes undergo genome reprogramming indicating terminal differentiation that can switch back to proliferation in contact with a stiffer environment.
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http://dx.doi.org/10.1007/s00403-019-01962-5DOI Listing
December 2019

Alteration of Pressure-Induced Vasodilation in Aging and Diabetes, a Neuro-Vascular Damage.

Front Physiol 2019 3;10:862. Epub 2019 Jul 3.

UMR 5305 CNRS, University of Lyon 1, Lyon, France.

Skin is constantly subjected to pressure at different levels. Pressure-induced vasodilation (PIV) is one of the response mechanisms to low pressure that maintains the homeostasis of the skin. PIV results from the interaction of primary afferent nerves and vascular endothelium of skin vessels. Thanks to this cutaneous neuro-vascular interaction, the cutaneous blood flow increase allows the maintenance of an optimal level of oxygenation and minimizes the lack of vascularization of the skin tissue under low pressure. It seems to be associated with the cutaneous protection mechanisms to prevent pressure ulcers. In some contexts, where microangiopathy and neuropathy can occur, such as aging and diabetes, PIV is impaired, leading to a dramatic early decrease in local skin blood flow when low pressure is applied. In aging, PIV alteration is due to endothelial dysfunction, essentially from an alteration of the nitric oxide pathway. In the inflamm-aging context, oxidative stress increases leading to endothelial cell and nerve damages. An age-related sensory neuropathy will exacerbate the alteration of PIV during the aging process. In diabetes, non-controlled hyperglycaemia leads to an increase in several pathological biochemical pathways that involve oxidative stress and can affect PIV. Sorbinil, alagebrium and alpha-lipoic acid are able individually to restore PIV through a possible oxidative stress reduction. Candesartan, an angiotensin II type 1 receptor blocker, is also able to restore PIV and prevent pressure ulcer formation. The possibility of preventing pressure ulcer associated to diabetes and/or aging with the restoration of PIV seems to be a promising research path.
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http://dx.doi.org/10.3389/fphys.2019.00862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616153PMC
July 2019

Neurovascular Response to Pressure in Patients With Diabetic Foot Ulcer.

Diabetes 2019 04 24;68(4):832-836. Epub 2019 Jan 24.

Laboratoire de Biologie Tissulaire et Ingénierie thérapeutique, UMR CNRS 5305, Lyon, France.

Diabetic foot ulcer (DFU) is a problem worldwide, and prevention is crucial. We hypothesized that the inability of the skin to respond to pressure is involved in DFU pathogenesis and could be an important predictive factor to take into account. We included 29 patients with DFU and 30 patients with type 2 diabetes without DFU. Neuropathy and skin blood flow at rest were assessed in response to acetylcholine, sodium nitroprusside, local heating (42°C), and to nonnoxious locally applied pressure. Results were compared with those obtained from 10 healthy age-matched control subjects. Vasodilatation in response to pressure was significantly impaired in both groups with diabetes compared with healthy subjects. The vasodilator capacity to pressure was significantly lower in patients with DFU compared with those without DFU, despite the absence of significant difference in cutaneous pressure perception threshold and vascular reactivity to acetylcholine, sodium nitroprusside, and heat. This pronounced alteration of neurovascular response to pressure in patients with DFU is a good marker of skin vulnerability and could be used to better predict individuals at risk.
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http://dx.doi.org/10.2337/db18-0694DOI Listing
April 2019

Altered blood rheology and impaired pressure-induced cutaneous vasodilation in a mouse model of combined type 2 diabetes and sickle cell trait.

Microvasc Res 2019 03 1;122:111-116. Epub 2018 Dec 1.

UMR 5305 CNRS, Lyon, France; Université de Lyon 1, UMR 5305, Lyon, France.

Objective: Type 2 diabetes (T2D)-related vascular dysfunction and hemorheological abnormalities could possibly be amplified by sickle cell trait (SCT). These alterations could potentially increase the risk of vascular complications in individuals with combined T2D and SCT. Therefore, this study used a mouse model to determine whether vascular function and blood rheology were more severely altered in combined T2D and SCT than in T2D or SCT alone.

Methods: Townes transgenic mice with or without SCT received a 12-week high fat high sucrose or standard diet to create models of combined T2D-SCT, T2D, SCT, and controls. Pressure-induced vasodilation (PIV) and sodium nitroprusside (SNP)-mediated vasodilation in-vivo, and hemorheological parameters were measured.

Results: No significant differences in blood viscosity, hematocrit, erythrocyte deformability, or PIV were observed between the control and T2D mice, or the control and SCT mice. However, blood viscosity, erythrocyte deformability, and PIV were significantly altered in the T2D-SCT mice compared to the control mice. There were no differences in SNP response between the groups.

Conclusions: Although neither T2D nor SCT alone had significant effects on blood rheology parameters or vascular function, combined T2D-SCT mice had significantly altered blood rheology and significantly impaired vascular function.
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http://dx.doi.org/10.1016/j.mvr.2018.11.014DOI Listing
March 2019

Skin microvascular dysfunction as an early cardiovascular marker in primary hyperoxaluria type I.

Pediatr Nephrol 2019 02 1;34(2):319-327. Epub 2018 Oct 1.

Centre de Référence des Maladies Rénales Rares, Service de Néphrologie et Rhumatologie Pédiatriques, Hospices Civils de Lyon, Lyon, France.

Background: Primary hyperoxaluria type 1 (PH1) is an orphan inborn error of oxalate metabolism leading to hyperoxaluria, progressive renal failure, oxalate deposition, and increased cardiovascular complications. As endothelial dysfunction and arterial stiffness are early markers of cardiovascular risk, we investigated early endothelial and vascular dysfunction in young PH1 patients either under conservative treatment (PH1-Cons) or after combined kidney liver transplantation (PH1-T) in comparison to healthy controls (Cont-H) and patients with a past of renal transplantation (Cont-T).

Methods: Skin microvascular function was non-invasively assessed by laser Doppler flowmetry before and after stimulation by current, thermal, or pharmacological (nitroprussiate (SNP) or acetylcholine (Ach)) stimuli in young PH1 patients and controls.

Results: Seven PH1-Cons (6 F, median age 18.2) and 6 PH1-T (2 F, median age 13.3) were compared to 96 Cont-H (51 F, median age 14.2) and 6 Cont-T (4 F, median age 14.5). The endothelium-independent vasodilatation (SNP) was severely decreased in PH1-T compared to Cont-H. Ach, current-induced vasodilatation (CIV), and thermal response was increased in PH1-Cons and Cont-T compared to controls.

Conclusions: PH1-T patients displayed severely decreased smooth muscle capacity to vasodilate. An exacerbated endothelial-dependent vasodilation suggests a role for silent inflammation in the early dysfunction of microcirculation observed in PH1-Cons and Cont-T.
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http://dx.doi.org/10.1007/s00467-018-4081-5DOI Listing
February 2019

Inflammation-linked adaptations in dermal microvascular reactivity accompany the development of obesity and type 2 diabetes.

Int J Obes (Lond) 2019 03 13;43(3):556-566. Epub 2018 Jul 13.

LBTI, UMR CNRS 5305, 69367, Lyon Cedex 07, France.

Background/objectives: The increased prevalence of obesity has prompted great strides in our understanding of specific adipose depots and their involvement in cardio-metabolic health. However, the impact of obesity on dermal white adipose tissue (dWAT) and dermal microvascular functionality remains unclear. This study aimed to investigate the temporal changes that occur in dWAT and dermal microvascular functionality during the development of diet-induced obesity and type 2 diabetes in mice.

Methods: Metabolic phenotyping of a murine model of hypercaloric diet (HCD)-induced obesity and type 2 diabetes was performed at three time points that reflected three distinct stages of disease development; 2 weeks of HCD-overweight-metabolically healthy, 4 weeks of HCD-obese-prediabetic and 12 weeks of HCD-obese-type 2 diabetic mice. Expansion of dWAT was characterized histologically, and changes in dermal microvascular reactivity were assessed in response to pressure and the vasodilators SNP and Ach.

Results: HCD resulted in a progressive expansion of dWAT and increased expression of pro-inflammatory markers (IL1β and COX-2). Impairments in pressure-induced (PIV) and Ach-induced (endothelium-dependent) vasodilation occurred early, in overweight-metabolically healthy mice. Residual vasodilatory responses were NOS-independent but sensitive to COX inhibition. These changes were associated with reductions in NO and adiponectin bioavailability, and rescued by exogenous adiponectin or hyperinsulinemia. Obese-prediabetic mice continued to exhibit impaired Ach-dependent vasodilation but PIV appeared normalized. This normalization coincided with elevated endogenous adiponectin and insulin levels, and was sensitive to NOS, COX and PI3K, inhibition. In obese-type 2 diabetic mice, both Ach-stimulated and pressure-induced vasodilatory responses were increased through enhanced COX-2-dependent prostaglandin response.

Conclusions: We demonstrate that the development of obesity, metabolic dysfunction and type 2 diabetes, in HCD-fed mice, is accompanied by increased dermal adiposity and associated metaflammation in dWAT. Importantly, these temporal changes are also linked to disease stage-specific dermal microvascular reactivity, which may reflect adaptive mechanisms driven by metaflammation.
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http://dx.doi.org/10.1038/s41366-018-0148-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223541PMC
March 2019

Sickle-cell trait and diagnosis of type 2 diabetes.

Lancet Diabetes Endocrinol 2018 11 17;6(11):840-843. Epub 2018 Feb 17.

Laboratoire Interuniversitaire de Biologie de la Motricité EA7424, Vascular Biology and the Red Blood Cell team, Université Claude Bernard Lyon 1, Université de Lyon 1, 6 Rue Raphaël Dubois, Villeurbanne 69100, France; Laboratoire d'Excellence GR-Ex, Paris, France; Institut Universitaire de France, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(18)30033-0DOI Listing
November 2018

Disruption of TRPV3 Impairs Heat-Evoked Vasodilation and Thermoregulation: A Critical Role of CGRP.

J Invest Dermatol 2018 03 17;138(3):688-696. Epub 2017 Oct 17.

Laboratoire de Biologie Tissulaire et Ingenierie therapeutique (LBTI) UMR 5305, CNRS-Université Lyon 1, Lyon, France.

Sensing environmental temperature is a key factor allowing individuals to maintain thermal homeostasis via thermoregulatory mechanisms, including changes to skin blood flow. Among transient receptor potential channels, transient receptor potential vanilloid 3 (TRPV3) is a heat-activated cation channel highly expressed in keratinocytes. However, the role of TRPV3 in triggering heat-evoked cutaneous vasodilation is unknown. Using a murine in vivo model of local acute environmental heat exposure in the skin, we show that TRPV3 is involved in the local thermoregulatory control of skin blood flow by initiating the release of calcitonin gene-related peptide and nitric oxide in response to local heating of the skin. In addition to their contribution in local heat-evoked vasodilation, TRPV3, calcitonin gene-related peptide, and nitric oxide also contribute to internal body temperature stability during passive whole-body heating. This study provides in vivo demonstration of the role of TRPV3 as a strong modulator of cutaneous vascular thermoregulatory mechanisms.
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http://dx.doi.org/10.1016/j.jid.2017.10.006DOI Listing
March 2018

Cutaneous and renal vasodilatory response to local pressure application: A comparative study in mice.

Microvasc Res 2018 01 30;115:44-51. Epub 2017 Aug 30.

Laboratory of Tissue Biology and Therapeutic Engineering, UMR 5305 CNRS, University Lyon 1, France; Néphrologie, Dialyse, Hypertension et Exploration Fonctionnelle Rénale, Groupement Hospitalier Edouard Herriot, Hospices Civils de Lyon, France; University Lyon 1, France. Electronic address:

Background And Aim: We have reported a novel relationship involving mechanical stimulation and vasodilation in rodent and human skin, referred to as pressure-induced vasodilation (PIV). It is unknown whether this mechanism exists in kidney and reflects the microcirculation in deep organs. Therefore, we compared the skin and kidney PIV to determine whether their changes were similar.

Methods: In anesthetized mice fed a normal salt-diet, laser Doppler flux (LDF) signals were measured when an increase in local pressure was applied to the surface of the head skin with the rate of 2.2Pa/s (1mmHg/min) and to the left kidney with a rate of 4.4Pa/s (2mmHg/min). The mechanism underlying renal PIV was also investigated. The skin and kidney PIV were also compared during salt load (4% NaCl diet).

Results: The kidney had higher baseline LDF and vascular conductance compared to those of the skin. Pressure application increased the LDF in the kidney as well as in the skin with a comparable maximal magnitude (about 25% from baseline value), despite different kinetics of PIV evolution. As we previously reported in the skin, the kidney PIV response was mediated by the activation of transient receptor potential vanilloid type 1 channels, the release of calcitonin gene-related peptide, and the participation of prostaglandins and nitric oxide. In the absence of hypertension, high salt intake abolished the cutaneous PIV response and markedly impaired the renal one.

Conclusion: PIV response in the mouse kidney results from a neuro-vascular interaction. Despite some differences between the skin and the kidney PIV, the similarities in their response and signaling mechanisms suggest that the cutaneous microcirculation could reflect, in part, the microcirculation of the renal cortex.
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http://dx.doi.org/10.1016/j.mvr.2017.08.007DOI Listing
January 2018

Amiloride treatment and increased risk of pressure ulcers in hospitalized patients.

Br J Clin Pharmacol 2016 12 18;82(6):1685-1687. Epub 2016 Sep 18.

Université Grenoble-Alpes, TIMC-IMAG, F-38000, Grenoble, France.

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http://dx.doi.org/10.1111/bcp.13084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099546PMC
December 2016

Sensory nerves contribute to cutaneous vasodilator response to cathodal stimulation in healthy rats.

Microvasc Res 2015 Sep 20;101:103-10. Epub 2015 Jul 20.

Laboratory of Tissue Biology and Therapeutic Engineering UMR5305 University of Lyon 1 and Centre National de la Recherche Scientifique (CNRS) IBCP, 7 passage du vercors 69367 Lyon cedex France; University of Lyon 1, UMR 5305, Lyon, France. Electronic address:

Cutaneous current-induced vasodilation (CIV) in response to galvanic current application is an integrative model of neurovascular interaction that relies on capsaicin-sensitive fiber activation. The upstream and downstream mechanisms related to the activation of the capsaicin-sensitive fibers involved in CIV are not elucidated. In particular, the activation of cutaneous transient receptor potential vanilloid type-1 (TRPV1) channels and/or acid-sensing ion channels (ASIC) (activators mechanisms) and the release of calcitonin gene-related peptide (CGRP) and substance P (SP) (effector mechanisms) have been tested. To assess cathodal CIV, we measured cutaneous blood flow using laser Doppler flowmetry for 20min following cathodal current application (240s, 100μA) on the skin of the thigh in anesthetized healthy rats for 20min. CIV was studied in rats treated with capsazepine and amiloride to inhibit TRPV1 and ASIC channels, respectively; CGRP8-37 and SR140333 to antagonize CGRP and neurokinin-1 (NK1) receptors, respectively; compared to their respective controls. Cathodal CIV was attenuated by capsazepine (12±2% vs 54±6%, P<0.001), amiloride (19±8% vs 61±6%, P<0.01), CGRP8-37 (15±6% vs 61±6%, P<0.001) and SR140333 (9±5% vs 54±6%, P<0.001) without changing local acidification. This is the first integrative study performed in healthy rats showing that cutaneous vasodilation in response to cathodal stimulation is initiated by activation of cutaneous TRPV1 and ASIC channels likely through local acidification. The involvement of CGRP and NK1 receptors suggests that cathodal CIV is the result of CGRP and SP released through activated capsaicin-sensitive fibers. Therefore cathodal CIV could be a valuable method to assess sensory neurovascular function in the skin, which would be particularly relevant to evaluate the presence of small nerve fiber disorders and the effectiveness of treatments.
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http://dx.doi.org/10.1016/j.mvr.2015.06.010DOI Listing
September 2015

Endothelium microenvironment sensing leading to nitric oxide mediated vasodilation: a review of nervous and biomechanical signals.

Nitric Oxide 2015 Feb 28;45:20-6. Epub 2015 Jan 28.

Laboratory of Tissue Biology and Therapeutic Engineering (LBTI), UMR5305 CNRS, University Lyon 1, Lyon, France. Electronic address:

Blood vessels are continuously exposed to various stresses such as mechanical strains and neurosignals. Besides its role as a barrier between blood and other tissues, the endothelium is a highly important cell layer for the regulation of vascular tone. Indeed, depending on the signal perceived by endothelial cells, it can drive a vasoconstrictor or vasodilator signal. This review presents mechano-receptors and neuro-receptors (restricted to neuropeptides) leading to vessel relaxation via the production of nitric oxide. Finally, some pieces of evidence of a potential cross-talk between these two kinds of stimuli are discussed.
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http://dx.doi.org/10.1016/j.niox.2015.01.006DOI Listing
February 2015

VEGF-A promotes both pro-angiogenic and neurotrophic capacities for nerve recovery after compressive neuropathy in rats.

Mol Neurobiol 2015 Feb 28;51(1):240-51. Epub 2014 May 28.

IBCP-UMR 5305 CNRS, 7 passage du Vercors, 69 367, Lyon Cedex 07, France,

Nerve recovery following injury is usually incomplete, leaving functional deficits. Our aim was to investigate the neural changes in pro-angiogenic, pro-inflammatory and apoptotic factors during and after chronic nerve compression (CNC). Nerve function was impaired after CNC and was progressively restored after nerve decompression, while nerve blood flow was elevated. While the expression of the pro-inflammatory and pro-angiogenic cytokines IL-6, TNF-α and VEGF-A was high during and after CNC, we observed that inhibition of VEGF-A receptors strongly counteracted the angiogenic response induced by the ex vivo CNC. Activation of the pro-survival transcription factor nuclear factor-kappa B (NF-κB) increased during CNC, returning to control levels after nerve decompression. After nerve decompression, the downregulation of Mdm2 correlated well with an increased expression of pro-apoptotic transcription factor p53. All together, we bring novel evidence that CNC activates transcription factors such as NF-κB and p53, which are key effectors of the cellular stress response, suggesting a neuroprotective process associated with an increased VEGF-A-mediated neurotrophic effect. Our results highlight the role of pro-angiogenic and pro-inflammatory cytokines during CNC that are reinforced by increasing neurotrophic capacity during recovery to promote nerve regeneration.
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http://dx.doi.org/10.1007/s12035-014-8754-1DOI Listing
February 2015

Effect of ageing on tactile transduction processes.

Ageing Res Rev 2014 Jan 26;13:90-9. Epub 2013 Dec 26.

Laboratory of Tissue Biology and Therapeutic Engineering, Centre National de la Recherche Scientifique (CNRS) UMR 5305, Lyon, France; University of Lyon 1, UMR 5305, Lyon, France. Electronic address:

With advancing age, a decline in the main sensory modalities including touch sensation and perception is well reported to occur. This review mainly outlines the peripheral components of touch perception highlighting ageing influences on morphological and functional features of cutaneous mechanical transducers and mechanosensitive ion channels, sensory innervation, neurotransmitters and even vascular system required to ensure efferent function of the afferent nerve fibres in the skin. This, in conjunction with effect of ageing on the skin per se and central nervous system, could explain the tactile deficit seen among the ageing population. We also discuss appropriate tools and experimental models available to study the age-related tactile decline.
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http://dx.doi.org/10.1016/j.arr.2013.12.003DOI Listing
January 2014

Severe sensory neuropathy increases risk of heel pressure ulcer in older adults.

J Am Geriatr Soc 2013 Nov;61(11):2050-2

Geriatrics Department, Bretonneau Hospital, Paris, France; Laboratory of Tissue Biology and Therapeutic Engineering, UMR CNRS 5305, University Claude Bernard Lyon 1, Lyon, France.

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http://dx.doi.org/10.1111/jgs.12532DOI Listing
November 2013

Skin microvascular response to pressure load in obese mice.

Microvasc Res 2013 Nov 9;90:138-43. Epub 2013 Oct 9.

UMR 5305 CNRS, 69 367 Lyon cedex 07, France; University of Lyon 1, 69 367 Lyon cedex 07, France.

Purpose: The role of obesity in the appearance of skin pressure ulcers remains controversial. The aim of the present study was to evaluate blood perfusion and related lesions after skin compression in obese mice.

Methods: Sixty C57BL6 male mice were randomly assigned to a control or hypercalorific diet (HCD) for 2, 4 and 12weeks. Skin compression was induced by a magnetic force of 11 kPa overlying a subcutaneous metal plate and applied for 4h. Skin perfusion was examined using laser Doppler imaging before skin compression, immediately after compression release and 24h later. 24h after magnet removal, skin injuries were determined by photography.

Results: A heterogeneous distribution of blood perfusion was observed using the colour-coded map of the skin perfusion on the compressed area. At 24-h post-compression release, 60% to 75% of the compressed area was ischaemic in the 2-week HCD group and in all the control groups compared to 35% in the 4- and 15% in the 12-week HCD groups. The lowest occurrence of skin lesion seen as skin redness or pressure-sores was observed in the 12- week HCD group (4%) compared to about 12% in either the control or the 2- and 4-week HCD groups.

Conclusions: This study suggests that there was no clear relationship between the extent of ischaemia and skin lesion occurrence after skin compression in short-duration obese mice. In contrast, it appears that long-duration obesity could reduce both ischaemia and skin lesions in response to skin compression through changes in skin structure.
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http://dx.doi.org/10.1016/j.mvr.2013.10.001DOI Listing
November 2013

Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers.

Nat Med 2012 Aug 29;18(8):1205-7. Epub 2012 Jul 29.

Institut de Biologie et Chimie des Protéines, Centre National de la Recherche Scientifique (CNRS) FRE 3310, Lyon, France; Université de Lyon 1, FRE 3310, Lyon, France.

Pressure-induced vasodilation (PIV) delays the decrease in cutaneous blood flow produced by local application of low pressure to the skin, a physiologically appropriate adjustment of local vasomotor function. Individuals without a normal PIV response have a high risk of ulceration. Here we demonstrate that acid-sensing ion channel 3 (Asic3) is an essential neuronal sensor for the vasodilation response to direct pressure in both humans and rodents and for protecting against pressure ulcers in mice.
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http://dx.doi.org/10.1038/nm.2844DOI Listing
August 2012

Chronic sciatic nerve injury impairs the local cutaneous neurovascular interaction in rats.

Pain 2012 Jan 3;153(1):149-157. Epub 2011 Nov 3.

Institut de biologie et chimie des protéines - FRE CNRS 3310, 69 367 Lyon, France University of Lyon 1, 69 367 Lyon, France UMR INSERM 1052 - CNRS 5286, 69 008 Lyon, France Laboratory of Ergonomics and Epidemiology in Health at Work, University of Angers, University Hospital, 49 933 Angers, France.

Most studies of chronic nerve compression focus on large nerve function in painful conditions, and only few studies have assessed potential changes in the function of small nerve fibers during chronic nerve compression and recovery from compression. Cutaneous pressure-induced vasodilation is a neurovascular phenomenon that relies on small neuropeptidergic fibers controlling the cutaneous microvasculature. We aimed to characterize potential changes in function of these small fibers and/or in cutaneous microvascular function following short-term (1-month) and long-term (6-month) nerve compression and after release of compression (ie, potential recovery of function). A compressive tube was left on one sciatic nerve for 1 or 6 months and then removed for 1-month recovery in Wistar rats. Cutaneous vasodilator responses were measured by laser Doppler flowmetry in hind limb skin innervated by the injured nerve to assess neurovascular function. Nociceptive thermal and low mechanical thresholds were evaluated to assess small and large nerve fiber functions, respectively. Pressure-induced vasodilation was impaired following nerve compression and restored following nerve release; both impairment and restoration were strongly related to duration of compression. Small and large nerve fiber functions were less closely related to duration of compression. Our data therefore suggest that cutaneous pressure-induced vasodilation provides a non-invasive and mechanistic test of neurovascular function that gives direct information regarding extent and severity of damage during chronic nerve compression and recovery, and may ultimately provide a clinically useful tool in the evaluation of nerve injury such as carpal tunnel syndrome.
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http://dx.doi.org/10.1016/j.pain.2011.10.001DOI Listing
January 2012

What can current stimulation tell us about the vascular function of endogenous prostacyclin in healthy rat skin in vivo?

J Invest Dermatol 2011 Jan 9;131(1):237-44. Epub 2010 Sep 9.

Neurovascular Interactions, FRE CNRS 3075, Institut des Sciences Biologiques et Pharmaceutiques, Université Claude Bernard Lyon 1, Lyon, France.

In endothelial function, prostacyclin (PGI(2)) is as important as nitric oxide (NO); however, no test assesses specifically the vascular function of endogenous PGI(2). We hypothesized that PGI(2) has a dominant role in cathodal current-induced vasodilation (CIV) described in human skin. We thus aimed to study, in physiological conditions, the PGI(2) involvement in cathodal CIV in rats in order to use pharmacological blockers that could not be used in humans. CIV was reduced by cyclooxygenase (COX)-1 and PGI(2) synthase (PGIS) and PGI(2) receptor (IP) blockers, but was unchanged by COX-2 and NO synthase (NOS) blockers. The level of 6-ketoPGF(1)(α) present in skin biopsies, measured as endogenous PGI(2), was increased by cathodal current stimulation, except under COX-1 and PGIS inhibition. This study provides evidence that cathodal CIV mainly relies on the release of PGI(2) endogenously produced through the COX-1/PGIS pathway, and then acts on IP receptors to relax the cutaneous microvessels in healthy rats. In contrast, neither COX-2 nor NOS is involved in CIV and the endogenous PGI(2) release by current stimulation. This finding shows that cathodal current stimulation could be a valuable method to assess the vascular function of endogenous PGI(2) in healthy skin.
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http://dx.doi.org/10.1038/jid.2010.267DOI Listing
January 2011

Aging-associated sensory neuropathy alters pressure-induced vasodilation in humans.

J Invest Dermatol 2010 Mar 3;130(3):849-55. Epub 2009 Sep 3.

Neurovascular Interactions, FRE CNRS 3075, University Claude Bernard Lyon 1, Département de Physilogie, Lyon, France.

Healthy skin is protected from pressure-induced ischemic damage because of the presence of pressure-induced vasodilation (PIV). PIV relies on small sensory nerve fibers and endothelial function. Since aging alters both nervous and vascular functions, we hypothesized that PIV is altered with aging. We compared PIV in non-neuropathic and neuropathic older subjects (60-75 years) with that of young subjects (20-35 years). Laser Doppler flowmetry was used to evaluate the cutaneous responses to local pressure application, acetylcholine, and local heating. Quantitative sensory tests were used to evaluate sensory-nerve-fiber function. The non-neuropathic older subjects had an impaired PIV (12+/-7% increase in blood flow with pressure) compared with young subjects (62+/-4%, P<0.001). In the presence of peripheral neuropathy, the older subjects were totally deprived of PIV, leading to early pressure-induced cutaneous ischemia (-31+/-10%, P<0.001). This inability of the skin to adapt to localized pressure in older subjects is related to the severity of the sensory-fiber dysfunction rather than to endothelial dysfunction, which was comparable between the non-neuropathic (141+/-19% increased blood flow with acetylcholine, P<0.05) and neuropathic older subjects (145+/-28% increase, P<0.05) compared with young subjects (234+/-25% increase).
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http://dx.doi.org/10.1038/jid.2009.279DOI Listing
March 2010

Axon-reflex cutaneous vasodilatation is impaired in type 2 diabetic patients receiving chronic low-dose aspirin.

Microvasc Res 2009 Sep 23;78(2):218-23. Epub 2009 Jun 23.

Laboratory of Vascular Investigations, University Hospital of Angers, France.

Low-dose aspirin is largely but non-homogeneously used in primary prevention of cardiovascular complication in type-2 diabetic patients. We hypothesised that low-dose aspirin could interfere with the cutaneous neurovascular responses in type-2 diabetic patients. Galvanic current-induced vasodilatation (CIV) is an original non-noxious integrative model of neurovascular interaction and is impaired under low-dose aspirin in healthy subjects. Twenty type-2 diabetic patients (ten not receiving aspirin: D(-NA) and ten regularly receiving
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http://dx.doi.org/10.1016/j.mvr.2009.06.005DOI Listing
September 2009

Multifractality in the peripheral cardiovascular system from pointwise holder exponents of laser Doppler flowmetry signals.

Biophys J 2007 Dec;93(12):L59-61

Groupe ISAIP-ESAIP, Saint Barthélémy d'Anjou, France.

We study the dynamics of skin laser Doppler flowmetry signals giving a peripheral view of the cardiovascular system. The analysis of Hölder exponents reveals that the experimental signals are weakly multifractal for young healthy subjects at rest. We implement the same analysis on data generated by a standard theoretical model of the cardiovascular system based on nonlinear coupled oscillators with linear couplings and fluctuations. We show that the theoretical model, although it captures basic features of the dynamics, is not complex enough to reflect the multifractal irregularities of microvascular mechanisms.
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http://dx.doi.org/10.1529/biophysj.107.119057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2098720PMC
December 2007

Endothelium-derived hyperpolarizing factor as an in vivo back-up mechanism in the cutaneous microcirculation in old mice.

J Physiol 2007 Dec 11;585(Pt 2):617-26. Epub 2007 Oct 11.

Integrative neuro-vascular biology, UMR CNRS 6214-INSERM 771, Medical School, University of Angers, France.

There is now strong evidence that an endothelium-derived hyperpolarizing factor (EDHF), other than nitric oxide (NO) or prostaglandin (PG), exists for dilating arteries and arterioles. In vitro studies on isolated vessels pointed out a role for EDHF as a back-up mechanism when the NO pathway is impaired, but there was a lack of in vivo studies showing a functional role for EDHF. Ageing has pronounced effects on vascular function and particularly on endothelium-dependent relaxation, providing a novel situation in which to assess the contributions of EDHF. The purpose of the present study was thus to determine if, in vivo, there was a functional role for EDHF as a back-up mechanism in the cutaneous microcirculation in the ageing process. We investigated in vivo the contribution of each endothelial factor (NO, PG and EDHF) in the cutaneous vasodilatation induced by iontophoretic delivery of acetylcholine and local pressure application in young adult (6-7 months) and old (22-25 months) mice, using pharmacological inhibitors. The cutaneous vasodilator responses induced by acetylcholine and local pressure application were dependent upon NO and PG pathways in young adult mice, whereas they were EDHF-dependent in old mice. EDHF appears to serve as a back-up mechanism when ageing reaches pathological states in terms of the ability for NO and PG to relax cutaneous microvessels, allowing for persistent cutaneous vasodilatator responses in old mice. However, as a back-up mechanism, EDHF did not completely restore cutaneous vasodilatation, since endothelial responses were reduced in old mice compared to young adult mice.
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http://dx.doi.org/10.1113/jphysiol.2007.143750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2375489PMC
December 2007

Altered acetylcholine, bradykinin and cutaneous pressure-induced vasodilation in mice lacking the TREK1 potassium channel: the endothelial link.

EMBO Rep 2007 Apr 9;8(4):354-9. Epub 2007 Mar 9.

Biologie Neuro-vasculaire Intégrée, UMR CNRS 6214-INSERM 771, Faculté de Médecine Angers, 49045 Angers, France.

The TWIK related K+ channel TREK1 is an important member of the class of two-pore-domain K+ channels. It is a background K+ channel and is regulated by hormones, neurotransmitters, intracellular pH and mechanical stretch. This work shows that TREK1 is present both in mesenteric resistance arteries and in skin microvessels. It is particularly well expressed in endothelial cells. Deletion of TREK1 in mice leads to an important alteration in vasodilation of mesenteric arteries induced by acetylcholine and bradykinin. Iontophoretic delivery of acetylcholine and bradykinin in the skin of TREK1+/+ and TREK1-/- mice also shows the important role of TREK1 in cutaneous endothelium-dependent vasodilation. The vasodilator response to local pressure application is also markedly decreased in TREK1-/- mice, mimicking the decreased response to pressure observed in diabetes. Deletion of TREK1 is associated with a marked alteration in the efficacy of the G-protein-coupled receptor-associated cascade producing NO that leads to major endothelial dysfunction.
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http://dx.doi.org/10.1038/sj.embor.7400916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852759PMC
April 2007

Neuroendocrine pathway involvement in the loss of the cutaneous pressure-induced vasodilatation during acute pain in rats.

J Physiol 2007 Feb 7;579(Pt 1):247-54. Epub 2006 Dec 7.

Integrative neuro-vascular biology, UMR CNRS 6214-INSERM 771, University of Angers, Rue Haute de Reculee, F-49045 Angers, France.

Pain is regarded as a risk factor in pressure ulcer development by contributing to immobility. Pressure-induced vasodilatation (PIV) is a mechanism whereby cutaneous blood flow increases in response to progressive locally applied pressure, thereby delaying the occurrence of ischaemia and appearing to be a protective response to local pressure. When the interaction between nervous and vascular systems is deregulated, PIV, which relies on both systems, is absent. We thus hypothesized that acute pain could alter PIV. This study investigated the effects on PIV of acute pain triggered by noxious heat (50 degrees C) applied to the tail of anaesthetized rats. To address the mechanisms underlying these effects, chronic sympathectomy was performed using guanethidine, and the plasma concentrations of pituitary adrenocorticotrophin (ACTH) and catecholamines were measured. Our results show that acute pain induces a loss of PIV associated with an increase of ACTH. Direct involvement of hypertensive effects and peripheral sympathetic nervous system are excluded in the loss of PIV, whereas the activation of brain structures that have descending inhibitory control cannot be excluded. A low dose of systemic morphine prevented this loss of PIV and maintained the ability of the cutaneous microcirculation to adapt to the applied pressure. The loss of a protective response to local pressure (PIV) induced by acute pain lends physiological support to the direct involvement of pain in pressure ulcer development. Therefore, an adequate evaluation and treatment of pain is crucial.
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http://dx.doi.org/10.1113/jphysiol.2006.121426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2075372PMC
February 2007