Controversies in the pathophysiology of leg ulcers in sickle cell disease.

Patients with sickle cell disease (SCD) often experience painful vaso-occlusive crises and chronic haemolytic anaemia, as well as various acute and chronic complications, such as leg ulcers. Leg ulcers are characterized by their unpredictability, debilitating pain and prolonged healing process. The pathophysiology of SCD leg ulcers is not well defined. Known risk factors include male gender, poor social conditions, malnutrition and a lack of compression therapy when oedema occurs. Leg ulcers typically start with spontaneous pain, followed by induration, hyperpigmentation, blister formation and destruction of the epidermis. SCD is characterized by chronic haemolysis, increased oxidative stress and decreased nitric oxide bioavailability, which promote ischaemia and inflammation and consequently impair vascular function in the skin. This cutaneous vasculopathy, coupled with venostasis around the ankle, creates an ideal environment for local vaso-occlusive crises, which can result in the development of leg ulcers that resemble arterial ulcers. Following the development of the ulcer, healing is hindered as a result of factors commonly observed in venous ulceration, including venous insufficiency, oedema and impaired angiogenesis. All of these factors are modulated by genetic factors. However, our current understanding of these genetic factors remains limited and does not yet enable us to accurately predict ulceration susceptibility.

Local heating-induced cutaneous vasodilation in reinnervated and noninnervated deep inferior epigastric perforator flaps.

INTRODUCTION: Cutaneous vascular reactivity to local heating in free flaps has not been characterized. We aimed to assess local heating-induced cutaneous vasodilation in reinnervated and noninnervated deep inferior epigastric perforator (DIEP) flaps. METHODS: We conducted a cross-sectional study of 21 female patients with an uncomplicated unilateral delayed DIEP breast reconstruction at least 2 years after surgery. DIEP flaps and contralateral breasts were subjected to direct local heating, and skin blood flow was assessed using laser-Doppler flowmetry. To evaluate sensory-nerve-fiber function, touch perception thresholds were assessed using a 20-piece Touch-test™ Sensory Evaluator, and cutaneous warm detection and heat pain thresholds were measured using a TSA-II device. RESULTS: Of the participants, 10 had a reinnervated DIEP flap with a single coapted nerve (mean flap weight, 610 ± 296 g) and 11 had a noninnervated DIEP flap (mean flap weight, 613 ± 169 g). Mean age was 58 ± 11 years, mean follow-up time was 5 ± 1 years, and mean BMI was 24 ± 3 kg/m2 . DIEP flaps exhibited significantly weaker cutaneous vasodilation in response to local heating than contralateral breasts (median peak skin blood flow, 59 [25th-75th percentile, 36-71] a.u. for DIEP flaps versus 94 [74-141] a.u. for contralateral breasts; p < .001). The magnitude of the response was similar between reinnervated and noninnervated flaps (median peak skin blood flow, 55 [25th-75th percentile, 39-68] a.u. for reinnervated DIEP flaps versus 66 [36-77] a.u. for noninnervated DIEP flaps; p = .75). Of participants with reinnervated DIEP flaps, 90% perceived heat pain below the 50°C safety threshold, as compared to 36% of participants with noninnervated DIEP flaps (two-tailed p = .02). CONCLUSION: Our results suggest that free flap transfer causes longstanding impairment, yet not complete abolition, of both the sensory nerve-mediated and nitric oxide-dependent local heating-induced cutaneous vasodilatory systems. We found no statistical evidence that flap reinnervation improves the ability to raise skin blood flow in response to local heating.

Dill Extract Preserves Dermal Elastic Fiber Network and Functionality: Implication of Elafin.

INTRODUCTION: Elastic skin fibers lose their mechanical properties during aging due to enzymatic degradation, lack of maturation, or posttranslational modifications. Dill extract has been observed to increase elastin protein expression and maturation in a 3D skin model, to improve mechanical properties of the skin, to increase elastin protein expression in vascular smooth muscle cells, to preserve aortic elastic lamella, and to prevent glycation. OBJECTIVE: The aim of the study was to highlight dill actions on elastin fibers during aging thanks to elastase digestion model and the underlying mechanism. METHODS: In this study, elastic fibers produced by dermal fibroblasts in 2D culture model were injured by elastase, and we observed the action of dill extract on elastic network by elastin immunofluorescence. Then action of dill extract was examined on mice skin by injuring elastin fibers by intradermal injection of elastase. Then elastin fibers were observed by second harmonic generation microscopy, and their functionality was evaluated by oscillatory shear stress tests. In order to understand mechanism by which dill acted on elastin fibers, enzymatic tests and real-time qPCR on cultured fibroblasts were performed. RESULTS: We evidence in vitro that dill extract is able to prevent elastin from elastase digestion. And we confirm in vivo that dill extract treatment prevents elastase digestion, allowing preservation of the cutaneous elastic network in mice and preservation of the cutaneous elastic properties. Although dill extract does not directly inhibit elastase activity, our results show that dill extract treatment increases mRNA expression of the endogenous inhibitor of elastase, elafin. CONCLUSION: Dill extract can thus be used to counteract the negative effects of elastase on the cutaneous elastic fiber network through modulation of PI3 gene expression.

In elderly Caucasian women, younger facial perceived age correlates with better forearm skin microcirculation reactivity.

BACKGROUND: Visual and molecular changes occurring upon aging are rather well characterized. Still, aging signs show great significant inter-individual variations, and little is known concerning the link between perceived age and cutaneous microcirculation. MATERIALS AND METHODS: To investigate this point, we recruited Caucasian women in their mid-50's to mid-70's and subsampled women looking older or younger than their age. We studied their facial skin color, as well as their microvascular reactivity to local heating assessed in the forearm skin. We also used skin biopsies from some of these women for gene expression or immunohistochemical analysis. RESULTS: Clinical and instrumental analysis of skin color revealed that subjects who look 5 years younger differ only by a higher glowing complexion. Our most striking result is that subjects looking 5 years younger than their age present a higher microcirculation reactivity in forearm skin. Transcriptome comparison of skin samples from women looking older or younger than their age revealed 123 annotated transcripts differentially expressed, among which MYL9 relates to microcirculation. MYL9 is downregulated in the group of women looking younger than their real age. Microscopy shows that the labeling of MYL9 and CD31 are altered and heterogeneous with age, as is the morphology of microvessels. CONCLUSION: Therefore, assessing generalized vascular reactivity in non-photo-exposed skin to focus on the intrinsic aging allows subtle discrimination of perceived age within elderly healthy subjects.

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

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 (IL1ß 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.

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

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.

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

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.

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

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.

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

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.

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

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.

Skin microvascular response to pressure load in obese mice.

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.

Aging is associated with impaired triggering of TRPV3-mediated cutaneous vasodilation: a crucial process for local heat exposure.

Sensing temperature is vitally important to adapt our body to environmental changes. Local warm detection is required to initiate regulation of cutaneous blood flow, which is part of the peripheral thermoregulatory mechanisms, and thus avoid damage to surrounding tissues. The mechanisms mediating cutaneous vasodilation during local heat stress are impaired with aging. However, the impact of aging on the ability of the skin to detect subtle thermal changes is unknown. Among heat-activated cation channels, transient receptor potential vanilloid 3 (TRPV3) is a thermo-sensor predominantly expressed on keratinocytes and involved in local vascular thermoregulatory mechanisms of the skin in young mice. In the present study, using a murine in vivo model of local heat exposure of the skin, we showed that heat-induced vasodilation was reduced in old mice associated with reduced expression of TRPV3 channels. We also found a decrease in expression and activity of TRPV3 channel, as well as reduced TRPV3-dependent adenosine tri-phosphate release in human primary keratinocytes from old donors. This study shows that aging alters the epidermal TRPV3 channels, which might delay the detection of changes in skin temperature, thereby limiting the mechanisms triggered for local vascular thermoregulation in the old skin.

Skin Cell and Tissue Responses to Cross-Linked Hyaluronic Acid in Low-Grade Inflammatory Conditions.

Hyaluronic acid (HA), used in a variety of medical applications, is associated in rare instances to long-term adverse effects. Although the aetiology of these events is unknown, a number of hypotheses have been proposed, including low molecular weight of HA (LMW-HA) in the filler products. We hypothesized that cross-linked HA and its degradation products, in a low-grade inflammatory microenvironment, could impact immune responses that could affect cell behaviours in the dermis. Using two different cross-linking technologies VYC-15L and HYC-24L+, and their hyaluronidase-induced degradation products, we observed for nondegraded HA, VYC-15L and HYC-24L+, a moderate and transient increase in IL-1ß, TNF-α in M1 macrophages under low-grade inflammatory conditions. Endothelial cells and fibroblasts were preconditioned using inflammatory medium produced by M1 macrophages. 24 h after LMW-HA fragments and HA stimulation, no cytokine was released in these preconditioned cells. To further characterize HA responses, we used a novel in vivo murine model exhibiting a systemic low-grade inflammatory phenotype. The intradermal injection of VYC-15L and its degradation products induced an inflammation and cell infiltration into the skin that was more pronounced than those by HYC-24L+. This acute cutaneous inflammation was likely due to mechanical effects due to filler injection and tissue integration rather than its biological effects on inflammation. VYC-15L and its degradation product potentiated microvascular response to acetylcholine in the presence of a low-grade inflammation. The different responses with 2D cell models and mouse model using the two tested cross-linking HA technologies showed the importance to use integrative complex model to better understand the effects of HA products according to inflammatory state.

Newborn and elderly skin: two fragile skins at higher risk of pressure injury.

Skin is a key organ maintaining internal homeostasis by performing many functions such as water loss prevention, body temperature regulation and protection from noxious substance absorption, microorganism intrusion and physical trauma. Skin ageing has been well studied and it is well known that physiological changes in the elderly result in higher skin fragility favouring the onset of skin diseases. For example, prolonged and/or high-intensity pressure may suppress local blood flow more easily, disturbing cell metabolism and inducing pressure injury (PI) formation. Pressure injuries (PIs) represent a significant problem worldwide and their prevalence remains too high. A higher PI prevalence is correlated with an elderly population. Newborn skin evolution has been less studied, but some data also report a higher PI prevalence in this population compared to older children, and several authors also consider this skin as physiologically fragile. In this review, we compare the characteristics of newborn and elderly skin in order to determine common features that may explain their fragility, especially regarding PI risk. We show that, despite differences in appearance, they share many common features leading to higher fragility to shear and pressure forces, not only at the structural level but also at the cellular and molecular level and in terms of physiology. Both newborn and elderly skin have: (i) a thinner epidermis; (ii) a thinner dermis containing a less-resistant collagen network, a higher collagen III:collagen I ratio and less elastin; (iii) a flatter dermal-epidermal junction (DEJ) with lower anchoring systems; and (iv) a thinner hypodermis, resulting in lower mechanical resistance to skin damage when pressure or shear forces are applied. At the molecular level, reduced expression of transforming growth factor ß (TGFß) and its receptor TGFß receptor II (TßRII) is involved in the decreased production and/or increased degradation of various dermal extracellular matrix (ECM) components. Epidermal fragility also involves a higher skin pH which decreases the activity of key enzymes inducing ceramide deficiency and reduced barrier protection. This seems to be correlated with higher PI prevalence in some situations. Some data also suggest that stratum corneum (SC) dryness, which may disturb cell metabolism, also increases the risk of PI formation. Besides this structural fragility, several skin functions are also less efficient. Low applied pressures induce skin vessel vasodilation via a mechanism called pressure-induced vasodilation (PIV). Individuals lacking a normal PIV response show an early decrease in cutaneous blood flow in response to the application of very low pressures, reflecting vascular fragility of the skin that increases the risk of ulceration. Due to changes in endothelial function, skin PIV ability decreases during skin ageing, putting it at higher risk of PI formation. In newborns, some data lead us to hypothesize that the nitric oxide (NO) pathway is not fully functional at birth, which may partly explain the higher risk of PI formation in newborns. In the elderly, a lower PIV ability results from impaired functionality of skin innervation, in particular that of C-fibres which are involved in both touch and pain sensation and the PIV mechanism. In newborns, skin sensitivity differs from adults due to nerve system immaturity, but the role of this in PIV remains to be determined.

Alpha-Lipoic Acid Supplementation Restores Early Age-Related Sensory and Endothelial Dysfunction in the Skin.

Many changes characterize skin aging, and the resulting dysfunctions still constitute a real challenge for our society. The aim of this study was to compare the skin aging of two rat strains, Wistar and Brown Norway (BN), considered as "poorly aging" and "healthy aging" models, respectively, and to assess the effect of alpha-lipoic acid (LPA), especially on skin microcirculation. To this purpose, various skin characteristics were studied at 6, 12, and 24 months and compared to the results of LPA treatment performed at 12 or 24 months. Skin aging occurred in both strains, but we showed an early occurrence of different age-related disorders in the Wistar strain compared to BN strain, especially regarding weight gain, glycemia dysregulation, basal skin perfusion, endothelial function, and skin resistance to low pressure. LPA treatment tended to improve skin resistance to low pressure in BN but not in Wistar despite the improvement of basal skin perfusion, endothelial function, and skin sensory sensitivity. Overall, this study confirmed the healthier aging of BN compared to Wistar strain and the positive effect of LPA on both general state and skin microcirculation.

[Functional integrity of aging skin, from cutaneous biology to anti-aging strategies]. / Vieillissement et intégrité de la peau - De la biologie cutanée aux stratégies anti-âge.

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.

TITLE: Vieillissement et intégrité de la peau - De la biologie cutanée aux stratégies anti-âge. ABSTRACT: La peau est un organe sentinelle, soumis au vieillissement chronologique et environnemental qui fragilise sa structure et ses fonctions. La fonction barrière de la peau, ses propriétés élastiques et de résistance, ainsi que sa réactivité vasculaire sont atteintes par le vieillissement dans les compartiments épidermiques, dermiques et vasculaires. Les progrès de la recherche ont permis de révéler des processus biologiques sous-jacents, qui peuvent être ciblés par des approches médicamenteuses topiques ou globales à base notamment d'anti-oxydants ou de sénolytiques. Ces stratégies anti-âge pourront contribuer à restaurer, au moins en partie, l'intégrité fonctionnelle de la peau âgée.

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

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.

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

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