Microgravity triggers ferroptosis and accelerates senescence in the MG-63 cell model of osteoblastic cells.

In space, cells sustain strong modifications of their mechanical environment. Mechanosensitive molecules at the cell membrane regulate mechanotransduction pathways that induce adaptive responses through the regulation of gene expression, post-translational modifications, protein interactions or intracellular trafficking, among others. In the current study, human osteoblastic cells were cultured on the ISS in microgravity and at 1 g in a centrifuge, as onboard controls. RNAseq analyses showed that microgravity inhibits cell proliferation and DNA repair, stimulates inflammatory pathways and induces ferroptosis and senescence, two pathways related to ageing. Morphological hallmarks of senescence, such as reduced nuclear size and changes in chromatin architecture, proliferation marker distribution, tubulin acetylation and lysosomal transport were identified by immunofluorescence microscopy, reinforcing the hypothesis of induction of cell senescence in microgravity during space flight. These processes could be attributed, at least in part, to the regulation of YAP1 and its downstream effectors NUPR1 and CKAP2L.

Mechanical strain induces a pro-fibrotic phenotype in human mitral valvular interstitial cells through RhoC/ROCK/MRTF-A and Erk1/2 signaling pathways.

The mitral valve is a complex multilayered structure populated by fibroblast-like cells, valvular interstitial cells (VIC) which are embedded in an extracellular matrix (ECM) scaffold and are submitted to the mechanical deformations affecting valve at each heartbeat, for an average of 40 million times per year. Myxomatous mitral valve (MMV) is the most frequent heart valve disease characterized by disruption of several valvular structures due to alterations of their ECM preventing the complete closure of the valve resulting in symptoms of prolapse and regurgitation. VIC and their ECM exhibit reciprocal dynamic processes between the mechanical signals issued from the ECM and the modulation of VIC phenotype responsible for ECM homeostasis of the valve. Abnormal perception and responsiveness of VIC to mechanical stress may induce an inappropriate adaptative remodeling of the valve progressively leading to MMV. To investigate the response of human VIC to mechanical strain and identify the molecular mechanisms of mechano-transduction in these cells, a cyclic equibiaxial elongation of 14% at the cardiac frequency of 1.16 Hz was applied to VIC by using a Flexercell-4000 T™ apparatus for increasing time (from 1 h to 8 h). We showed that cyclic stretch induces an early (1 h) and transient over-expression of TGFß2 and αSMA. CTGF, a profibrotic growth factor promoting the synthesis of ECM components, was strongly induced after 1 and 2 h of stretching and still upregulated at 8 h. The mechanical stress-induced CTGF up-regulation was dependent on RhoC, but not RhoA, as demonstrated by siRNA-mediated silencing approaches, and further supported by evidencing RhoC activation upon cell stretching and suppression of cell response by pharmacological inhibition of the effector ROCK1/2. It was also dependent on the MEK/Erk1/2 pathway which was activated by mechanical stress independently of RhoC and ROCK. Finally, mechanical stretching induced the nuclear translocation of myocardin related transcription factor-A (MRTF-A) which forms a transcriptional complex with SRF to promote the expression of target genes, notably CTGF. Treatment of stretched cultures with inhibitors of the identified pathways (ROCK1/2, MEK/Erk1/2, MRTF-A translocation) blocked CTGF overexpression and abrogated the increased MRTF-A nuclear translocation. CTGF is up-regulated in many pathological processes involving mechanically challenged organs, promotes ECM accumulation and is considered as a hallmark of fibrotic diseases. Pharmacological targeting of MRTF-A by newly developed inhibitors may represent a relevant therapy for MMV.

Propranolol sensitizes prostate cancer cells to glucose metabolism inhibition and prevents cancer progression.

Propranolol, a widely used non-selective beta-adrenergic receptor blocker, was recently shown to display anticancer properties. Its potential to synergize with certain drugs has been also outlined. However, it is necessary to take into account all the properties of propranolol to select a drug that could be efficiently combined with. Propranolol was reported to block the late phase of autophagy. Hence, we hypothesized that in condition enhancing autophagy flux, cancer cells should be especially sensitive to propranolol. 2DG, a glycolysis inhibitor, is an anti-tumor agent having limited effect in monotherapy notably due to induction of pro-survival autophagy. Here, we report that treatment of cancer cells with propranolol in combination with the glycolysis inhibitor 2DG induced a massive accumulation of autophagosome due to autophagy blockade. The propranolol +2DG treatment efficiently prevents prostate cancer cell proliferation, induces cell apoptosis, alters mitochondrial morphology, inhibits mitochondrial bioenergetics and aggravates ER stress in vitro and also suppresses tumor growth in vivo. Our study underlines for the first time the interest to take advantage of the ability of propranolol to inhibit autophagy to design new anti-cancer therapies.

Circulating microRNAs signature correlates with positive [18F]fluorodeoxyglucose-positron emission tomography in patients with abdominal aortic aneurysm.

BACKGROUND: Prediction of abdominal aortic aneurysm (AAA) rupture is a challenging issue. Small noncoding microRNAs (miRNAs) are potent regulators of gene expression and are considered as valuable circulating biomarkers. Recently, [18F]fluorodeoxyglucose (FDG) uptake detected by positron emission tomography (PET) in AAA was correlated with cellular and molecular alterations involved in wall instability and its potential rupture. Our study aimed at identifying circulating miRNAs correlated with a positive PET that could help discriminate patients at high risk of rupture. METHODS: The level of 372 miRNAs was evaluated by polymerase chain reaction array in plasma from 35 AAA patients displaying no FDG uptake (A0) and 22 patients with a positive PET uptake (A+). The modulated miRNAs were validated by quantitative polymerase chain reaction and measured in aneurysmal tissues from both groups of patients. RESULTS: Six circulating miRNAs were found significantly modulated in A+ vs A0 patients. They were significantly correlated not only between them but also with the intensity of FDG uptake. Two of them correlated also with the AAA diameter. These miRNAs displayed significant discriminating power between the A+ and A0 groups as determined by receiver operating characteristic curves. Three downregulated circulating miRNAs (miR-99b-5p, miR-125b-5p, and miR-204-5p) were also significantly reduced in the aneurysmal tissue, specifically in the FDG-uptake site, compared with a negative zone in the same aneurysm and with A0 aneurysms. They were further significantly inversely correlated with the expression, at the positive uptake site, of some of their potential gene targets, most notably matrix metalloproteinase 13. CONCLUSIONS: Six miRNAs were identified as potential new circulating biomarkers of PET+ AAA. Three of these were similarly modulated in the metabolically active aneurysmal wall and might be directly involved in AAA instability.

Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF-ß signaling as primary targets.

A disintegrin and metalloproteinase with thrombospondin type I motif (ADAMTS)2, 3, and 14 are collectively named procollagen N-proteinases (pNPs) because of their specific ability to cleave the aminopropeptide of fibrillar procollagens. Several reports also indicate that they could be involved in other biological processes, such as blood coagulation, development, and male fertility, but the potential substrates associated with these activities remain unknown. Using the recently described N-terminal amine isotopic labeling of substrate approach, we analyzed the secretomes of human fibroblasts and identified 8, 17, and 22 candidate substrates for ADAMTS2, 3, and 14, respectively. Among these newly identified substrates, many are components of the extracellular matrix and/or proteins related to cell signaling such as latent TGF-ß binding protein 1, TGF-ß RIII, and dickkopf-related protein 3. Candidate substrates for the 3 ADAMTS have been biochemically validated in different contexts, and the implication of ADAMTS2 in the control of TGF-ß activity has been further demonstrated in human fibroblasts. Finally, the cleavage site specificity was assessed showing a clear and unique preference for nonpolar or slightly hydrophobic amino acids. This work shows that the activities of the pNPs extend far beyond the classically reported processing of the aminopropeptide of fibrillar collagens and that they should now be considered as multilevel regulators of matrix deposition and remodeling.-Bekhouche, M., Leduc, C., Dupont, L., Janssen, L., Delolme, F., Vadon-Le Goff, S., Smargiasso, N., Baiwir, D., Mazzucchelli, G., Zanella-Cleon, I., Dubail, J., De Pauw, E., Nusgens, B., Hulmes, D. J. S., Moali, C., Colige, A. Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF-ß signaling as primary targets.

18F-FDG PET/CT in the Management of Aortitis.

BACKGROUND: Aortitis is a generic term defined as an inflammatory condition involving the aortic wall, of infectious or noninfectious origin. This inflammatory process may deteriorate the aortic wall, resulting in potentially life-threatening vascular complications. Therefore, it is important to establish a diagnosis as early as possible. PATIENTS AND METHODS: During a 4-year period, 428 consecutive patients referred to our department for aortic diseases underwent FDG PET/CT examinations. Among these, 18 patients (4.2%) were suspected to have aortitis. All of them had an initial positive FDG PET/CT uptake occurring in the aorta and major branches as evaluated by visual analysis of images and assessed with the final diagnosis of aortitis. During follow-up, after surgery and/or upon immunosuppressive treatment, each of these patients underwent a second PET/CT that was compared with the initial evaluation. In all cases, normalization of FDG uptake was correlated with clinical improvement. CONCLUSIONS: Our study aimed to illustrate the potential clinical value of functional monitoring with PET/CT in the management of aortitis. FDG PET/CT constitutes a valuable imaging modality to establish an early diagnosis, monitor disease progression and treatment, and evaluate vascular complication and relapse. We highlight the importance of an early detection of inflammatory large-vessel pathology, which may represent a major threat.

Elastin density: Link between histological and biomechanical properties of vaginal tissue in women with pelvic organ prolapse?

INTRODUCTION AND HYPOTHESIS: The aim of the study was to correlate histological and biomechanical characteristics of the vaginal wall in women with pelvic organ prolapse (POP). METHODS: Tissue samples were collected from the anterior [point Ba; POP Questionnaire (POP-Q)] and/or posterior (point Bp; POP-Q) vaginal wall of 15 women who underwent vaginal surgery for POP. Both histological and biomechanical assessments were performed from the same tissue samples in 14 of 15 patients. For histological assessment, the density of collagen and elastin fibers was determined by combining high-resolution virtual imaging and computer-assisted digital image analysis. For biomechanical testing, uniaxial tension tests were performed to evaluate vaginal tissue stiffness at low (C0) and high (C1) deformation rates. RESULTS: Biomechanical testing highlights the hyperelastic behavior of the vaginal wall. At low strains (C0), vaginal tissue appeared stiffer when elastin density was low. We found a statistically significant inverse relationship between C0 and the elastin/collagen ratio (p = 0.048) in the lamina propria. However, at large strain levels (C1), no clear relationship was observed between elastin density or elastin/collagen ratio and stiffness, likely reflecting the large dispersion of the mechanical behavior of the tissue samples. CONCLUSION: Histological and biomechanical properties of the vaginal wall vary from patient to patient. This study suggests that elastin density deserves consideration as a relevant factor of vaginal stiffness in women with POP.

RhoGTPases as key players in mammalian cell adaptation to microgravity.

A growing number of studies are revealing that cells reorganize their cytoskeleton when exposed to conditions of microgravity. Most, if not all, of the structural changes observed on flown cells can be explained by modulation of RhoGTPases, which are mechanosensitive switches responsible for cytoskeletal dynamics control. This review identifies general principles defining cell sensitivity to gravitational stresses. We discuss what is known about changes in cell shape, nucleus, and focal adhesions and try to establish the relationship with specific RhoGTPase activities. We conclude by considering the potential relevance of live imaging of RhoGTPase activity or cytoskeletal structures in order to enhance our understanding of cell adaptation to microgravity-related conditions.

Skin physiology in microgravity: a 3-month stay aboard ISS induces dermal atrophy and affects cutaneous muscle and hair follicles cycling in mice.

AIMS: The Mice Drawer System (MDS) Tissue Sharing program was the longest rodent space mission ever performed. It provided 20 research teams with organs and tissues collected from mice having spent 3 months on the International Space Station (ISS). Our participation to this experiment aimed at investigating the impact of such prolonged exposure to extreme space conditions on mouse skin physiology. METHODS: Mice were maintained in the MDS for 91 days aboard ISS (space group (S)). Skin specimens were collected shortly after landing for morphometric, biochemical, and transcriptomic analyses. An exact replicate of the experiment in the MDS was performed on ground (ground group (G)). RESULTS: A significant reduction of dermal thickness (-15%, P=0.05) was observed in S mice accompanied by an increased newly synthetized procollagen (+42%, P=0.03), likely reflecting an increased collagen turnover. Transcriptomic data suggested that the dermal atrophy might be related to an early degradation of defective newly formed procollagen molecules. Interestingly, numerous hair follicles in growing anagen phase were observed in the three S mice, validated by a high expression of specific hair follicles genes, while only one mouse in the G controls showed growing hairs. By microarray analysis of whole thickness skin, we observed a significant modulation of 434 genes in S versus G mice. A large proportion of the upregulated transcripts encoded proteins related to striated muscle homeostasis. CONCLUSIONS: These data suggest that a prolonged exposure to space conditions may induce skin atrophy, deregulate hair follicle cycle, and markedly affect the transcriptomic repertoire of the cutaneous striated muscle panniculus carnosus.

Gene expression study in positron emission tomography-positive abdominal aortic aneurysms identifies CCL18 as a potential biomarker for rupture risk.

Rupture of abdominal aortic aneurysm (AAA) is a cause of significant mortality and morbidity in aging populations. Uptake of 18-fluorodeoxyglucose (FDG) detected by positron emission tomography (PET) is observed in the wall of 12% of AAA (A+), with most of them being symptomatic. We previously showed that the metabolically active areas displayed adventitial inflammation, medial degeneration and molecular alterations prefacing wall rupture. The aim of this study was to identify new factors predictive of rupture. Transcriptomic analyses were performed in the media and adventitia layers from three types of samples: AAA with-out FDG uptake (A0) and with FDG uptake (A+), both at the positive spot (A+(Pos)) and at a paired distant negative site (A+(Neg)) of the same aneurysm. Follow-up studies included reverse-transcriptase-polymerase chain reaction (RT-PCR), immunohistochemical staining and enzyme-linked immunosorbent assay (ELISA). A large number of genes, including matrix metalloproteinases, collagens and cytokines as well as genes involved in osteochondral development, were differentially expressed in the A+(Pos) compared with A+(Neg). Moreover, a series of genes (notably CCL18) was differentially expressed both in the A+(Neg) and A+(Pos) compared with the A0. A significant increase of CCL18 was also found at the protein level in the aortic wall and in peripheral blood of A+ patients compared with A0. In conclusion, new factors, including CCL18, involved in the progression of AAA and, potentially, in their rupture were identified by a genome-wide analysis of PET-positive and -negative human aortic tissue samples. Further work is needed to study their role in AAA destabilization and weakening.

Rac1 GTPase silencing counteracts microgravity-induced effects on osteoblastic cells.

Bone cells exposed to real microgravity display alterations of their cytoskeleton and focal adhesions, two major mechanosensitive structures. These structures are controlled by small GTPases of the Ras homology (Rho) family. We investigated the effects of RhoA, Rac1, and Cdc42 modulation of osteoblastic cells under microgravity conditions. Human MG-63 osteoblast-like cells silenced for RhoGTPases were cultured in the automated Biobox bioreactor (European Space Agency) aboard the Foton M3 satellite and compared to replicate ground-based controls. The cells were fixed after 69 h of microgravity exposure for postflight analysis of focal contacts, F-actin polymerization, vascular endothelial growth factor (VEGF) expression, and matrix targeting. We found that RhoA silencing did not affect sensitivity to microgravity but that Rac1 and, to a lesser extent, Cdc42 abrogation was particularly efficient in counteracting the spaceflight-related reduction of the number of focal contacts [-50% in silenced, scrambled (SiScr) controls vs. -15% for SiRac1], the number of F-actin fibers (-60% in SiScr controls vs. -10% for SiRac1), and the depletion of matrix-bound VEGF (-40% in SiScr controls vs. -8% for SiRac1). Collectively, these data point out the role of the VEGF/Rho GTPase axis in mechanosensing and validate Rac1-mediated signaling pathways as potential targets for counteracting microgravity effects.

Vascular Endothelial Growth Factor-111 (VEGF-111) and tendon healing: preliminary results in a rat model of tendon injury.

Tendon lesions are among the most frequent musculoskeletal pathologies. Vascular endothelial growth factor (VEGF) is known to regulate angiogenesis. VEGF-111, a biologically active and proteolysis-resistant splice variant of this family, was recently identified. This study aimed at evaluating whether VEGF-111 could have a therapeutic interest in tendon pathologies. Surgical section of one Achilles tendon of rats was performed before a local injection of either saline or VEGF-111. After 5, 15 and 30 days, the Achilles tendons of 10 rats of both groups were sampled and submitted to a biomechanical tensile test. The force necessary to induce tendon rupture was greater for tendons of the VEGF-111 group (p<0.05) while the section areas of the tendons were similar. The mechanical stress was similar at 5 and 15 days in the both groups but was improved for the VEGF-111 group at day 30 (p <0.001). No difference was observed in the mRNA expression of collagen III, tenomodulin and MMP-9. In conclusion, we observed that a local injection of VEGF-111 improves the early phases of the healing process of rat tendons after a surgical section. Further confirmatory experimentations are needed to consolidate our results.

Changes in elastin density in different locations of the vaginal wall in women with pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: The purpose of this study was to analyze the histomorphometric properties of the vaginal wall in women with pelvic organ prolapse (POP). METHODS: In 15 women undergoing surgery for POP, full-thickness biopsies were collected at two different sites of location from the anterior and/or posterior vaginal wall. Properties of the precervical area (POP-Q point C/D) were compared with the most distal portion of the vaginal wall (POP-Q point Ba/Bp) using histological staining and immunohistochemistry. The densities of total collagen fibers, elastic fibers, smooth muscle cells, and blood vessels were determined by combining high-resolution virtual imaging and computer-assisted digital image analysis. RESULTS: The mean elastin density was significantly decreased in the lamina propria and muscularis layer of the vaginal wall from the most distal portion of the prolapsed vaginal wall compared with the precervical area. This difference was statistically significant in the lamina propria for both anterior (8.4 ± 1.2 and 12.1 ± 2.0, p = 0.048) and posterior (6.8 ± 0.5 and 10.1 ± 1.4, p = 0.040) locations, and in the muscularis for the anterior (5.2 ± 0.4 and 8.4 ± 1.2, p = 0.009) vaginal wall. There were no statistically significant differences in the mean densities of collagen fibers, smooth muscle cells or blood vessels between the two locations. CONCLUSIONS: In this study, we observed changes in elastin density in two different locations of the vaginal wall from women with POP. The histomorphometric properties of the vaginal wall can be variable from one place to another in the same patient. This result supports the existence of most vulnerable locations within the vaginal wall and the potential benefit of site-specific prolapse surgery.

18F-FDG uptake assessed by PET/CT in abdominal aortic aneurysms is associated with cellular and molecular alterations prefacing wall deterioration and rupture.

UNLABELLED: Rupture of abdominal aortic aneurysms (AAAs) leads to a significant morbidity and mortality in aging populations, and its prediction would be most beneficial to public health. Spots positive for uptake of (18)F-FDG detected by PET are found in 12% of AAA patients (PET+), who are most often symptomatic and at high rupture risk. Comparing the (18)F-FDG-positive site with a negative site from the same aneurysm and with samples collected from AAA patients with no (18)F-FDG uptake should allow the discrimination of biologic alterations that would help in identifying markers predictive of rupture. METHODS: Biopsies of the AAA wall were obtained from patients with no (18)F-FDG uptake (PET0, n = 10) and from PET+ patients (n = 8), both at the site positive for uptake and at a distant negative site of the aneurysmal wall. Samples were analyzed by immunohistochemistry, quantitative real-time polymerase chain reaction, and zymography. RESULTS: The sites of the aneurysmal wall with a positive (18)F-FDG uptake were characterized by a strikingly increased number of adventitial inflammatory cells, highly proliferative, and by a drastic reduction of smooth muscle cells (SMCs) in the media as compared with their negative counterpart and with the PET0 wall. The expression of a series of genes involved in the maintenance and remodeling of the wall was significantly modified in the negative sites of PET+, compared with the PET0 wall, suggesting a systemic alteration of the aneurysmal wall. Furthermore, a striking increase of several matrix metalloproteinases (MMPs), notably the MMP1 and MMP13 collagenases, was observed in the positive sites, mainly in the adventitia. Moreover, PET+ patients were characterized by a higher circulating C-reactive protein. CONCLUSION: Positive (18)F-FDG uptake in the aneurysmal wall is associated with an active inflammatory process characterized by a dense infiltrate of proliferating leukocytes in the adventitia and an increased circulating C-reactive protein. Moreover, a loss of SMC in the media and alterations of the expression of genes involved in the remodeling of adventitia and collagen degradation potentially participate in the weakening of the aneurysmal wall preceding rupture.

Effects of mild cold shock (25°C) followed by warming up at 37°C on the cellular stress response.

Temperature variations in cells, tissues and organs may occur in a number of circumstances. We report here that reducing temperature of cells in culture to 25°C for 5 days followed by a rewarming to 37°C affects cell biology and induces a cellular stress response. Cell proliferation was almost arrested during mild hypothermia and not restored upon returning to 37°C. The expression of cold shock genes, CIRBP and RBM3, was increased at 25°C and returned to basal level upon rewarming while that of heat shock protein HSP70 was inversely regulated. An activation of pro-apoptotic pathways was evidenced by FACS analysis and increased Bax/Bcl2 and BclX(S/L) ratios. Concomitant increased expression of the autophagosome-associated protein LC3II and AKT phosphorylation suggested a simultaneous activation of autophagy and pro-survival pathways. However, a large proportion of cells were dying 24 hours after rewarming. The occurrence of DNA damage was evidenced by the increased phosphorylation of p53 and H2AX, a hallmark of DNA breaks. The latter process, as well as apoptosis, was strongly reduced by the radical oxygen species (ROS) scavenger, N-acetylcysteine, indicating a causal relationship between ROS, DNA damage and cell death during mild cold shock and rewarming. These data bring new insights into the potential deleterious effects of mild hypothermia and rewarming used in various research and therapeutical fields.

Histology of the vaginal wall in women with pelvic organ prolapse: a literature review.

INTRODUCTION AND HYPOTHESIS: The pathophysiology of pelvic organ prolapse (POP) is incompletely understood. The purpose of this study is to describe the current knowledge about histology of the vaginal wall and its possible involvement in the pathogenesis of pelvic organ prolapse. METHODS: Eligible studies were selected through a MEDLINE search covering January 1986 to December 2012. The research was limited to English-language publications. RESULTS: Investigations of changes in the vaginal tissue that occur in women with genital prolapse are currently still limited and produced contrary results. The heterogeneity of the patients and the control groups in terms of age, parity and hormonal status, of the localization of biopsies and the histological methods as well as the lack of validation of the quantification procedures do not allow clear and definitive conclusions to be drawn. CONCLUSIONS: This review shows that current knowledge of the histological changes observed in women with POP are inconclusive and relatively limited. More studies are needed in this specific field to better understand the mechanisms that lead to POP.

Emerging pathogenic mechanisms in human myxomatous mitral valve: lessons from past and novel data.

INTRODUCTION: Myxomatous mitral valve is one of the most common heart valves diseases in human and has been well characterized at a functional and morphological level. Diseased valves are thickened as a result of extracellular matrix remodeling and proteoglycans accumulation accompanied by the disruption of the stratified structures of the leaflets. METHODS: Global transcriptomic analysis was used as a start-up to investigate potential pathogenic mechanisms involved in the development of the human idiopathic myxomatous mitral valve, which have been elusive for many years. RESULTS: These prospective analyses have highlighted the potential role of apparently unrelated molecules in myxomatous mitral valve such as members of the transforming growth factor-ß superfamily, aggrecanases of the "a disintegrin and metalloprotease with thrombospondin repeats I" family, and a weakening of the protection against oxidative stress. We have integrated, in this review, recent transcriptomic data from our laboratory [A. Hulin, C.F. Deroanne, C.A. Lambert, B. Dumont, V. Castronovo, J.O. Defraigne, et al. Metallothionein-dependent up-regulation of TGF-beta2 participates in the remodelling of the myxomatous mitral valve. Cardiovasc Res 2012;93:480-489] and from the publication of Sainger et al. [R. Sainger, J.B. Grau, E. Branchetti, P. Poggio, W.F. Seefried, B.C. Field, et al. Human myxomatous mitral valve prolapse: role of bone morphogenetic protein 4 in valvular interstitial cell activation. J Cell Physiol 2012;227:2595-2604] with existing literature and information issued from the study of monogenic syndromes and animal models. CONCLUSION: Understanding cellular alterations and molecular mechanisms involved in myxomatous mitral valve should help at identifying relevant targets for future effective pharmacological therapy to prevent or reduce its progression.

Eccentric training improves tendon biomechanical properties: a rat model.

The treatment of choice for tendinopathies is eccentric reeducation. Although the clinical results appear favorable, the biomechanical changes to the tissue are not yet clear. Even if the mechanotransduction theory is commonly accepted, the physiology of tendons is not clearly understood. We aimed to better define the biomechanical and histological changes that affect healthy tendon after eccentric and concentric training. This study compared the effects of two methods of training (eccentric [E] training and concentric [C] training) with untrained (U) rats. The animals were trained over a period of 5 weeks. The tricipital, patellar, and Achilles tendons were removed, measured and a tensile test until failure was performed. A histological analysis (hematoxylin and eosin and Masson's trichrome stains) was also realized. There was a significant increase in the rupture force of the patellar and tricipital tendons between the U and E groups. The tricipital tendons in the control group presented a significantly smaller cross-sectional area than the E- and C-trained groups, but none was constated between E and C groups. No significant difference was observed for the mechanical stress between the three groups for all three tendons. Histological studies demonstrated the development of a greater number of blood vessels and a larger quantity of collagen in the E group. The mechanical properties of tendons in rats improve after specific training, especially following eccentric training. Our results partly explained how mechanical loading, especially in eccentric mode, could improve the healing of tendon.

Dissection of Iliac Artery in a Patient With Autosomal Dominant Polycystic Kidney Disease: A Case Report.

Autosomal dominant polycystic kidney disease (ADPKD) is a risk factor for several cardiovascular disorders such as intracranial aneurysm or aortic dissection, preferentially occurring at the thoracic or abdominal level. A 47-year-old man suffering from ADPKD had renal transplantation. Sixteen hours after surgery, he presented with left leg pain. Clinical and ultrasound examination revealed thrombosis of the external left iliac artery. Therefore, we decided to perform intra-arterial angiography to evaluate the possibility of an endovascular treatment. Aorto-femorography showed an obstruction of the external left iliac artery that was found during emergency surgery, consecutive to a dissection, which occurred following the surgery for kidney transplantation. The resected segment of the dissected vessel was analyzed by histology. Collagen fibers organization and density in the adventitia and smooth muscle cells density in the media were similar in the dissected and a normal artery from a healthy donor. By contrast, an almost complete disappearance and fragmentation of elastic lamellae were observed in the media of the dissected artery, most likely responsible for the weakening of the arterial wall and its dissection. Association between ADPKD and single dissection of the iliac artery has been rarely reported. Relationship between inactivation of polycystin/PKD genes and elastic fibers degradation through elevated TGFß signaling and matrix metalloproteinase 2 (MMP2) elastolytic activity, as recently reported in ADPKD, would be worth investigating.