Smooth Muscle Cell Growth Research Articles

(084) Analysis of BMP4 and GREMLIN as targets of SHH signaling and regulators of the collagen axis in the penis.

Abstract Introduction Increased collagen deposition occurs in erectile dysfunction (ED) patients and animal models, and the underlying causes of these fibrotic changes have not been well defined. The Sonic hedgehog (SHH) pathway is critical for the response of the penis to denervation. Decreased SHH in the penis due to cavernous nerve (CN) injury, causes smooth muscle apoptosis and ED. As smooth muscle is lost, increased collagen occurs by a largely unknown mechanism. We have shown that collagen abundance is responsive to SHH signaling in the penis. Microarray analysis identified increased GREMLIN (BMP4 antagonist) in corpora cavernosa of ED patients, and SHH is a regulator of GREMLIN in the limb bud. Objective We hypothesize that SHH regulation of collagen occurs through a BMP4/GREMLIN dependent mechanism and will examine BMP4 and GREMLIN signalling in corpora cavernosa of ED patients and a rat prostatectomy model. Study of how collagen induction occurs after prostatectomy would be useful to determine the underlying mechanism of penile remodeling. Methods Corpora cavernosal tissue (n=36) from prostatectomy, diabetic and Peyronie’s (control) patients were examined by immunohistochemical and western analysis for BMP-4 and GREMLIN proteins. Localization was determined by dual staining with ACTA2 and CD31. Collagen was quantified by hydroxyproline assay and trichrome stain with Image J analysis. Primary cultures of patient corpora cavernosa were established and treated with BMP4 and GREMLIN proteins, and smooth muscle cell growth was quantified. Sprague dawley rat penis was treated in vivo with SHH protein by peptide amphiphile, 5E1 SHH inhibitor, BMP4 and GREMLIN via Affi-Gel beads. Collagen was quantified. Results BMP-4 and GREMLIN were identified in smooth muscle of Peyronie’s, prostatectomy and diabetic ED patients. Western analysis identified increased BMP4 and GREMLIN proteins in prostatectomy and diabetic patients where collagen is increased. Primary culture of corpora cavernosal smooth muscle cells showed an increase in growth with BMP4 and decreased growth with GREMLIN treatment. This trend was more pronounced in cells from hypertension and cardiovascular disease patients. BMP4 and GREMLIN proteins increased 1-2 days after CN injury in a rat prostatectomy model that showed decreasing SHH in the penis. SHH inhibition in the penis increases BMP4, GREMLIN and collagen. SHH treatment of the penis after CN injury in the rat decreases collagen, BMP4 and GREMLIN. Conclusions SHH is decreased in corpora cavernosa of prostatectomy and diabetic ED patients while BMP4 and GREMLIN are increased. Decreased SHH increases BMP4 protein and collagen, suggesting a possible mechanism for fibrotic penile remodelling after CN injury. This study is the first step in understanding the mechanism of how SHH regulates collagen abundance in the penis, which is important for clinical translation. Disclosure No

MALT1 accelerates proatherogenic vascular smooth muscle cell growth, invasion and synthetic phenotype switching via nuclear factor‑κB signaling‑dependent way.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) modulates T helper cell differentiation and nuclear factor-κB (NF-κB) pathway-mediated inflammation and potentially regulates lipid metabolism, which are all critical factors involved in atherosclerosis. The present study aimed to investigate the effect of MALT1 on the cellular functions of proatherogenic vascular smooth muscle cells (VSMCs). Therefore, to establish a human proatherogenic VSMC model, VSMCs were treated with different doses of oxidized low-density lipoprotein (oxLDL). Subsequently, the effect of MALT1 overexpression or knockdown in proatherogenic VSMCs treated with or without NF-κB activator was also explored. The results showed that treatment of proatherogenic VSMCs with oxLDL significantly elevated the mRNA and protein expression levels of MALT1 in a dose-dependent manner. Furthermore, MALT1 overexpression enhanced cell viability, invasion and phenotype switching and reduced apoptosis in proatherogenic VSMCs. However, MALT1 knockdown exerted the opposite effect on the above cellular functions. Additionally, the results revealed that MALT1 could positively regulate the NF-κB pathway in proatherogenic VSMCs. Moreover, treatment of proatherogenic VSMCs with NF-κB activator not only exacerbated the dysregulation of cellular functions, but also hampered the effect of MALT1 knockdown on attenuating cell growth, invasion and synthetic phenotype switching, thus suggesting that NF-κB was essential for the regulation of MALT1-triggered functions in proatherogenic VSMCs. In conclusion, the current study suggested that MALT1 could exacerbate cell viability, mobility and synthetic phenotype switching of proatherogenic VSMCs in a NF-κB signaling-dependent manner. Therefore, MALT1 could be considered as a potential therapeutic target for atherosclerosis.

Perivascular Adipose Tissue and Vascular Smooth Muscle Tone: Friends or Foes?

Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue that surrounds most mammalian blood vessels. PVAT is a metabolically active, endocrine organ capable of regulating blood vessel tone, endothelium function, vascular smooth muscle cell growth and proliferation, and contributing critically to cardiovascular disease onset and progression. In the context of vascular tone regulation, under physiological conditions, PVAT exerts a potent anticontractile effect by releasing a plethora of vasoactive substances, including NO, H2S, H2O2, prostacyclin, palmitic acid methyl ester, angiotensin 1-7, adiponectin, leptin, and omentin. However, under certain pathophysiological conditions, PVAT exerts pro-contractile effects by decreasing the production of anticontractile and increasing that of pro-contractile factors, including superoxide anion, angiotensin II, catecholamines, prostaglandins, chemerin, resistin, and visfatin. The present review discusses the regulatory effect of PVAT on vascular tone and the factors involved. In this scenario, dissecting the precise role of PVAT is a prerequisite to the development of PVAT-targeted therapies.

The effect of Nano-liposomal sodium nitrite on smooth muscle cell growth in a tissue-engineered small-diameter vascular graft.

Nitric oxide is a chemical agent produced by endothelial cells in a healthy blood vessel, inhibiting the overgrowth of vascular smooth muscle cells and regulating vessel tone. Liposomes are biocompatible and biodegradable drug carriers with a similar structure to cell bilayer phospholipid membrane that can be used as useful nitric oxide carriers in vascular grafts. Using a custom-designed apparatus, the sheep carotid arteries were decellularized while still maintaining important components of the vascular extracellular matrix (ECM), allowing them to be used as small-diameter vascular grafts. A chemical signal of sodium nitrite was applied to control smooth muscle cells' behavior under static and dynamic cell culture conditions. The thin film hydration approach was used to create nano-liposomes, which were then used as sodium nitrite carriers to control the drug release rate and enhance the amount of drug loaded into the liposomes. The ratio of 80:20:2 for DPPC: Cholesterol: PEG was determined as the optimum formulation of the liposome structure with high drug encapsulation efficiency (98%) and optimum drug release rate (the drug release rate was 40%, 65%, and 83% after 24, 48, and 72h, respectively). MTT assay results showed an improvement in endothelial cell proliferation in the presence of nano-liposomal sodium nitrite (LNS) at the concentration of 0.5μg/mL. Using a suitable concentration of liposomal sodium nitrite (0.5μg/mL) put onto the constructed scaffold resulted in the controllable development of smooth muscle cells in the experiment. The culture of smooth muscle cells in a pulsatile perfusion bioreactor indicated that in the presence of synthesized liposomal sodium nitrite, the overgrowth of smooth muscle cells was inhibited in dynamic cell culture conditions. The mechanical properties of ECM graft were measured, and a multi-scale model with an accuracy of 83% was proposed to predict mechanical properties successfully. The liposomal drug-loaded small-diameter vascular graft can prevent the overgrowth of SMCs and the formation of intimal hyperplasia in the graft. Aside from that, the effect of LNS on endothelial has the potential to stimulate endothelial cell proliferation and re-endothelialization.

Piranha solution treatment: A facile method for improving the antithrombotic ability and regulating smooth muscle cell growth on blood contact materials.

Blood contact materials require strong anti-fouling capabilities to avoid thrombus formation. Recently, TiO2-based photocatalytic antithrombotic treatment has gained focus. Nevertheless, this method is restricted to titanium materials with photocatalytic abilities. This study offers an alternative solution that can be applied to a broader range of materials: piranha solution treatment. Our findings revealed that the free radicals generated by the treatment effectively altered the surface physicochemical properties of various inorganic materials, enhancing their surface hydrophilicity and oxidizing organic contaminants, thus improving their antithrombotic properties. Additionally, the treatment resulted in contrasting effects on the cellular affinity of SS and TiO2. While it significantly reduced the adhesion and proliferation of SMCs on SS surfaces, it significantly enhanced these on TiO2 surfaces. These observations suggested that the impact of the piranha solution treatment on the cellular affinity of biomaterials was closely tied to the intrinsic properties of the materials. Thus, materials suitable for piranha solution treatment could be selected based on the functional requirements of implantable medical devices. In conclusion, the broad applicability of piranha solution surface modification technology in both blood-contact and bone implant materials highlights its promising prospects.

Inhibition of human detrusor smooth muscle cell growth and modulation of cytoskeletal organization by Immuno-Modulatory Imide Drugs (IMIDs)

Inhibition of human detrusor smooth muscle cell growth and modulation of cytoskeletal organization by Immuno-Modulatory Imide Drugs (IMIDs)

Myocd regulates airway smooth muscle cell remodeling in response to chronic asthmatic injury.

Abnormal growth of airway smooth muscle cells is one of the key features in asthmatic airway remodeling, which is associated with asthma severity. The mechanisms underlying inappropriate airway smooth muscle cell growth in asthma remain largely unknown. Myocd has been reported to act as a key transcriptional coactivator in promoting airway-specific smooth muscle development in fetal lungs. Whether Myocd controls airway smooth muscle remodeling in asthma has not been investigated. Mice with lung mesenchyme-specific deletion of Myocd after lung development were generated, and a chronic asthma model was established by sensitizing and challenging the mice with ovalbumin for a prolonged period. Comparison of the asthmatic pathology between the Myocd knockout mice and the wild-type controls revealed that abrogation of Myocd mitigated airway smooth muscle cell hypertrophy and hyperplasia, accompanied by reduced peri-airway inflammation, decreased fibrillar collagen deposition on airway walls, and attenuation of abnormal mucin production in airway epithelial cells. Our study indicates that Myocd is a key transcriptional coactivator involved in asthma airway remodeling. Inhibition of Myocd in asthmatic airways may be an effective approach to breaking the vicious cycle of asthmatic progression, providing a novel strategy in treating severe and persistent asthma. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Toward Synthetic Vascular Graft Monitoring Using a Flip-Chip-on-Flex Impedance Spectroscopy Sensor

Synthetic vascular grafts are used in a wide range of clinical applications. However, they can become prone to occlusion over time, due to the growth of vascular smooth muscle cells (VSMCs). This phenomenon is associated with graft failure. Here, we describe novel techniques for packaging and integration of a miniature sensor of VSMC growth. The sensor was based on a microfabricated array of interdigitated platinum electrodes on a silicon substrate. It was assembled using flip-chip-on-flex (FCOF) technology to create a low-profile package that can be manufactured using industry-standard tools and is suitable for integration with a synthetic vascular graft. The packaged sensor responded to changes in solution impedance and accurately detected the growth of VSMC in vitro. We also demonstrated successful proof-of-concept integration of the sensor with a custom synthetic graft. Together these technologies have the potential to allow early detection of VSMC growth prior to graft occlusion, enabling more timely and effective clinical interventions to be made.

USP15 promotes pulmonary vascular remodeling in pulmonary hypertension in a YAP1/TAZ-dependent manner

Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disease characterized by pulmonary vascular remodeling. Excessive growth and migration of pulmonary artery smooth muscle cells (PASMCs) are believed to be major contributors to pulmonary vascular remodeling. Ubiquitin-specific protease 15 (USP15) is a vital deubiquitinase that has been shown to be critically involved in many pathologies. However, the effect of USP15 on PH has not yet been explored. In this study, the upregulation of USP15 was identified in the lungs of PH patients, mice with SU5416/hypoxia (SuHx)-induced PH and rats with monocrotaline (MCT)-induced PH. Moreover, adeno-associated virus-mediated functional loss of USP15 markedly alleviated PH exacerbation in SuHx-induced mice and MCT-induced rats. In addition, the abnormal upregulation and nuclear translocation of YAP1/TAZ was validated after PH modeling. Human pulmonary artery smooth muscle cells (hPASMCs) were exposed to hypoxia to mimic PH in vitro, and USP15 knockdown significantly inhibited cell proliferation, migration, and YAP1/TAZ signaling in hypoxic hPASMCs. Rescue assays further suggested that USP15 promoted hPASMC proliferation and migration in a YAP1/TAZ-dependent manner. Coimmunoprecipitation assays indicated that USP15 could interact with YAP1, while TAZ bound to USP15 after hypoxia treatment. We further determined that USP15 stabilized YAP1 by inhibiting the K48-linked ubiquitination of YAP1. In summary, our findings reveal the regulatory role of USP15 in PH progression and provide novel insights into the pathogenesis of PH.

Ferroptotic stress facilitates smooth muscle cell dedifferentiation in arterial remodelling by disrupting mitochondrial homeostasis.

Smooth muscle cell (SMC) phenotypic switch from a quiescent 'contractile' phenotype to a dedifferentiated and proliferative state underlies the development of cardiovascular diseases (CVDs); however, our understanding of the mechanism is still incomplete. In the present study, we explored the potential role of ferroptosis, a novel nonapoptotic form of cell death, in SMC phenotypic switch and related neointimal formation. We found that ferroptotic stress was triggered in cultured dedifferentiated SMCs and arterial neointimal tissue of wire-injured mice. Moreover, pro-ferroptosis stress was activated in arterial neointimal tissue of clinical patients who underwent carotid endarterectomy. Blockade of ferroptotic stress via administration of a pharmacological inhibitor or by global genetic overexpression of glutathione peroxidase-4 (GPX4), a well-established anti-ferroptosis molecule, delayed SMC phenotype switch and arterial remodelling. Conditional SMC-specific gene delivery of GPX4 using adreno-associated virus in the carotid artery inhibited ferroptosis and prevented neointimal formation. Conversely, ferroptosis stress directly triggered dedifferentiation of SMCs. Transcriptomics analysis demonstrated that inhibition of ferroptotic stress mainly targets the mitochondrial respiratory chain and oxidative phosphorylation. Mechanistically, ferroptosis inhibition corrected the disrupted mitochondrial homeostasis in dedifferentiated SMCs, including enhanced mitochondrial ROS production, dysregulated mitochondrial dynamics, and mitochondrial hyperpolarization, and ultimately inhibited SMC phenotypic switch and growth. Copper-diacetyl-bisN4-methylthiosemicarbazone (CuATSM), an agent used for clinical molecular imaging and that potently inhibits ferroptosis, prevented SMC phenotypic switch, neointimal formation and arterial inflammation in mice. These results indicate that pro-ferroptosis stress is likely to promote SMC phenotypic switch during neointimal formation and imply that inhibition of ferroptotic stress may be a promising translational approach to treat CVDs with SMC phenotype switch.

MiR-140-3p Ameliorates The Inflammatory Response of Airway Smooth Muscle Cells by Targeting HMGB1 to Regulate The JAK2/STAT3 Signaling Pathway.

The growth and migration of airway smooth muscle cells (ASMCs) are dysregulated in asthma. MicroRNAs (miRNAs) are associated with the pathogenesis of many diseases including asthma. Instead, the function of miR-140- 3pin ASMCs' dysregulation in asthma remains inconclusive. This study aimed to explore the role and mechanism of miR-140-3p in ASMCs' dysregulation. In this experimental study, ASMCs were stimulated with platelet-derived growth factor (PDGF)- BB to construct an asthma cell model in vitro. MiR-140-3p expression level in the plasma of 50 asthmatic patients and 50 healthy volunteers was measured with quantitative real-time polymerase chain reaction (qRT-PCR). Besides, the enzyme-linked immunosorbent assay (ELISA) was applied to detect the contents of interleukin (IL) -1β, IL-6, and tumor necrosis factor-α (TNF-α) in the cell culture supernatant of ASMCs. Additionally, CCK-8 and transwell assays were adopted to probe the multiplication and migration of ASMCs. In addition, the western blot was employed to examine HMGB1, JAK2, and STAT3 protein expressions in ASMCs after miR-140-3p and HMGB1 were selectively regulated. miR-140-3p expression was declined in asthmatic patients' plasma and ASMCs stimulated by PDGF-BB. Upregulating miR-140-3p suppressed the viability and migration of the cells and alleviated the inflammatory response while inhibiting miR-140-3p showed opposite effects. Additionally, HMGB1 was testified as the target of miR-140-3p. HMGB1 overexpression could reverse the impact of miR-140-3p upregulation on the inflammatory response of ASMCs stimulated by PDGF-BB. MiR-140-3p could repress the activation of JAK2/STAT3 via suppressing HMGB1. In ASMCs, miR-140-3p can inhibit the JAK2/STAT3 signaling pathway by targeting HMGB1, thus ameliorating airway inflammation and remodeling in the pathogenesis of asthma.

WEB-BASED EXPERT SYSTEM TO DIAGNOSE OVARIAL CYST DISEASE USING CERTAINTY FACTOR METHOD

Ovarian cysts are one of the most common forms of reproductive disease affecting women. Cyst or tumor is a form of abnormality that can be regarded as a benign growth of smooth muscle cells in the ovaries. Cysts are usually harmless but do not rule out the possibility of a malignant cyst or even turn into cancer. The thing that makes ovarian cysts dangerous is when they burst, are very large, or block the blood supply to the ovaries. Lack of knowledge of the general public about the symptoms that cause ovarian cyst disease makes it too late to detect this disease early so it is slow in handling, there are even some cysts or tumors which when they become malignant are only detected as having ovarian cysts, as well as unhealthy lifestyles of today's society such as consuming alcohol, fast food, causing the body to produce more chemicals. To overcome this problem, the design of a web-based expert system to diagnose ovarian cyst disease using the certainty factor method is made to assist the public or users in diagnosing through the symptoms they feel. The method used to diagnose ovarian cyst disease is the Certainty Factor method. From the calculations that have been inputted by the user, the results obtained are 97% confidence that the patient is likely to be diagnosed with cystadenoma ovarii mucinosum. With this web-based expert system program, it is hoped that the general public or users can diagnose ovarian cyst disease through the symptoms felt so as to minimize the possibility of the cyst becoming malignant.

Photolithographically Patterned Cell-Repellent PEG-b-PTHPMA Diblock Copolymer for Guided Cell Adhesion and Growth.

Surfaces for guided cell adhesion and growth are indispensable in several diagnostic and therapeutic applications. Towards this direction, four diblock copolymers comprising polyethylene glycol (PEG) and poly(2-tetrahydropyranyl methacrylate) (PTHPMA) are synthesized employing PEG macroinitiators of different chain lengths. The copolymer with a 5000Da PEG block and a PEG-PTHPMA comonomers weight ratio of 43-57 provides a film with the highest stability in the culture medium and the strongest cell repellent properties. This copolymer is used to develop a positive photolithographic material and create stripe patterns onto silicon substrates. The highest selectivity regarding smooth muscle cell adhesion and growth and the highest fidelity of adhered cells for up to 3 days in culture is achieved for stripe patterns with widths between 25 and 27.5µm. Smooth muscle cells cultured on such patterned substrates exhibit a decrease in their proliferation rate and nucleus area and an increase in their major axis length, compared to the cells cultured onto non-patterned substrates. These alterations are indicative of the adoption of a contractile rather than a synthetic phenotype of the smooth muscle cells grown onto the patterned substrates and demonstrate the potential of the novel photolithographic material and patterning method for guided cell adhesion and growth.

Quercetin inhibits angiotensin II-induced vascular smooth muscle cell proliferation and activation of JAK2/STAT3 pathway: A target based networking pharmacology approach.

The rapid growth of vascular smooth muscle cells (VSMCs) represents crucial pathological changes during the development of hypertensive vascular remodeling. Although quercetin exhibits significantly therapeutic effects on antihypertension, the systematic role of quercetin and its exact mode of action in relation to the VSMCs growth and its hypertension-related networking pharmacology is not well-documented. Therefore, the effect of quercetin was investigated using networking pharmacology followed by in vitro strategies to explore its efficacy against angiotensin II (Ang II)-induced cell proliferation. Putative genes of hypertension and quercetin were collected using database mining, and their correlation was investigated. Subsequently, a network of protein-protein interactions was constructed and gene ontology (GO) analysis was performed to identify the role of important genes (including CCND1) and key signaling pathways [including cell proliferation and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway]. We therefore further investigated the effects of quercetin in Ang II-stimulated VSMCs. This current research revealed that quercetin significantly reduced the cell confluency, cell number, and cell viability, as well as expression of proliferating cell nuclear antigen (PCNA) in Ang II-stimulated VSMCs. Mechanistic study by western blotting confirmed that quercetin treatment attenuated the activation of JAK2 and STAT3 by reducing its phosphorylation in Ang II stimulated VSMCs. Collectively, the current study revealed the inhibitory effects of quercetin on proliferation of Ang II stimulated VSMCs, by inhibiting the activation of JAK2/STAT3 signaling might be one of underlying mechanisms.

Silencing myostatin increases area fraction of smooth muscle in the corpus cavernosum of pigs

Myostatin (MSTN), an inhibitor of skeletal muscle growth, is also expressed in penile smooth muscle; however, it is unclear whether MSTN plays an inhibitory role in penile smooth muscle growth. We investigated the role of MSTN in the smooth muscle of the penile corpus cavernosum of pigs using MSTN homozygous mutant knockout (KO) and wild type (WT) pigs (n = 4 in each group). The mean of area fraction (%) of smooth muscle in the penile corpus cavernosum was 65.9 % ± 1.79 in the KO and approximately 41.7 % ± 5.39 in the WT (P < 0.001). KO pigs showed significantly increased expression of smooth muscle-specific genes, including smooth muscle protein 22 (TAGLN) (6.62-fold), smooth muscle myosin heavy chain (MYH11) (2.41-fold), myocardin (MYOCD) (3.05-fold), and serum response factor (SRF) (4.95-fold), and decreased expression of vimentin (VIM) (1.36-fold). Immunofluorescence staining and Western blotting showed smooth muscle-specific expression of α-smooth muscle actin (SMA) and calponin was higher in KO pigs (P < 0.05) than in WT pigs. KO pigs had less fat deposition inside the corpus cavernosum, and showed downregulation of adiponectin (ADIPOQ) and fatty acid synthase (FASN) (2.5-fold and 1.9-fold loss, respectively). In vitro experiments showed MSTN interference promoted corporal smooth muscle cell growth and expression of smooth muscle-specific markers, whereas it downregulated the expression of fat-specific genes, ADIPOQ and FASN. MSTN inhibition could promote smooth muscle growth and decrease fat deposition in the corpus cavernosum. MSTN, thus, could be a possible target for the treatment of smooth muscle dystrophy-related disorders such as erectile dysfunction.

One-step fabrication of self-healing poly(thioctic acid) coatings on ZE21B Mg alloys for enhancing corrosion resistance, anti-bacterial/oxidation, hemocompatibility and promoting re-endothelialization

Coating magnesium (Mg) alloy stents with biodegradable polymeric materials can address the problems of thrombosis, inflammation, and restenosis caused by poor corrosion resistance and delayed endothelialization; however, these commonly used polymer coatings and their degradation products have no therapeutic effect and sometimes bring extra-side effects. Herein, to develop a polymeric coating with an additional therapeutic effect from that of the polymer itself, a poly(thioctic acid)-based homopolymer was simply synthesized via solvent-free thermal polymerization (containing Zn2+ ions) of thioctic acid (TA), a bioactive ingredient originating from the human body. A Poly(TA-Zn) coating was fabricated on alkali-heat (Mg(OH)2) treated ZE21B alloys via a one-step method, followed by conjugating REDV peptides, to simultaneously enhance the corrosion resistance and re-endothelialization process. Surface characterization and performance were comprehensively investigated. Molecular dynamics (MD) simulations demonstrate that the Zn-O coordination bonds formed between Zn2+ ions and carboxylic groups can inhibit the depolymerization of the Poly(TA-Zn) polymer. SEM micrographs show that the Poly(TA-Zn) coating is homogeneous and has a thickness of 45.03 ± 4.85 μm, and this coating is sturdily bonded to the Mg(OH)2 modified ZE21B substrate. Electrochemical and immersion tests show that the Poly(TA-Zn) sample provides good corrosion protection for ZE21B substrates because of its excellent self-healing properties, and it exhibits superior anti-bacterial/oxidation properties. After immobilizing REDV peptides, Poly(TA-Zn)-REDV samples can substantially hinder platelet adhesion/activation, reduce hemolysis rate, selectively promote the proliferation of endothelial cells and inhibit the growth of smooth muscle cells, thereby improving the anti-coagulation and re-endothelialization ability of Mg substrates.

Intravenous leiomyomatosis of the uterus: still discovered on anatomopathological examination

Background: Leiomyomas beyond the uterus are defined by benign smooth muscle cell tumors outside of the uterus. Intravenous leiomyomatosis is a rare type of uterine leiomyoma and is characterized by the formation and growth of benign leiomyoma tissue within the vascular wall. Herein, we present a case of Intravenous leiomyomatosis successfully treated by surgical removal and a review of actual medical recommendations. Case presentation: A 49 - year-old woman, maghrébin, G3 P2, no family history of uterine myomas mentioned, having systemic arterial hypertension, presented to our department with hypogastric pain and abnormal uterine bleeding in the prior five months resulting in anemia which required iron supplementation. On physical examination the vital signs were normal. A palpable mass in the hypogastrium was noted. The rest of the exam was unremarkable. Pelvic ultrasound showed a huge uterus with multiple heterogeneous leiomyomas, including at least one intracavity. Computed tomography scans and magnetic resonance imaging were not done initially due to the unaffordability of the patient. The initial diagnosis was leiomyoma. The decision to perform a total abdominal hysterectomy and bilateral salpingo-oophorectomy was taken. The abdomen was opened by a midline vertical incision. During surgery, multiple subserosal, intramural and submucosal fibroids ranging from 2 cm × 3 cm to 10 cm × 10 cm were seen. On pathological examination, the uterus measured 19 cm in the largest diameter and weighed 1.3 kg. The cut section showed white nodular myometrial masses. Microscopically, intravascular growth of benign smooth muscle cells is found within venous channels lined by endothelium. The diagnosis of Intravenous leiomyomatosis of the uterus without malignant transformation was retained. The patient was monitored for 14 months and subsequent computed tomography did not reveal any evidence of tumor recurrence. The follow-up will be performed annually till the age of menopause. Conclusion: Intravenous leiomyomatosis is a benign, rare and potentially lethal pathology. It especially affects premenopausal women with a history of uterine myoma, whether operated on or not. They require close and prolonged follow-up because of the high risk of recurrence.

Endothelin-1 alters BMP signaling to promote proliferation of pulmonary artery smooth muscle cells.

Pulmonary arterial hypertension (PAH) is characterized by abnormal outgrowth of pulmonary artery smooth muscle cells (PASMCs) of the media. Abundant expression of endothelin-1 (ET-1) and activated p38 mitogen-activated protein kinase (p38MAPK) has been observed in PAH patients. p38MAPK has been implicated in cell proliferation. An unspecified disturbance in bone morphogenetic protein (BMP) signaling may be involved in the development of PAH. Type I receptors (BMPR1A and BMPR1B) and type II receptor (BMPR2) transduce signals via two distinct pathways, i.e., canonical and non-canonical pathways, activating Smad1/5/8 and p38MAPK, respectively. BMPR1B expression was previously reported to be enhanced in the PASMCs of patients with idiopathic PAH. BMP15 binds specifically to BMPR1B. We assessed the effects of ET-1 on BMP receptor expression and cell proliferation. BMP2 increased BMPR1B expression in human PASMCs after pretreatment with ET-1 in vitro. Although BMP2 alone did not affect PASMC proliferation, BMP2 treatment after ET-1 pretreatment significantly accelerated PASMC proliferation. PH-797804, a selective p38MAPK inhibitor, abrogated this proliferation. Similarly, after ET-1 pretreatment, BMP15 significantly accelerated the proliferation of PASMCs, whereas stimulation with BMP15 alone did not. In conclusion, in PASMCs, ET-1 exposure under pathological conditions alters BMP signaling to activate p38MAPK, resulting in cell proliferation.

NORAD Promotes the Viability, Migration, and Phenotypic Switch of Human Vascular Smooth Muscle Cells during Aortic Dissection via LIN28B-Mediated TGF-β Promotion and Subsequent Enhanced Glycolysis.

Glucose metabolism reprogramming is an important reason for the functional remodeling, growth, and migration of vascular smooth muscle cells (VSMCs). It is also an important basis for the occurrence and development of aortic dissection (AD), but the specific regulatory factors are not clear. Noncoding RNA activated by DNA damage (NORAD) is dysfunctional in many diseases, but the role of NORAD in AD etiology is unclear. We first established a vascular remodeling cell model of AD, and the expression of NORAD in VSMCs was significantly increased. Functional experiments showed that inhibition of NORAD could downregulate the proliferation and migration of VSMCs. Meanwhile, silencing NORAD could also inhibit the flux of glycolysis, suggesting that NORAD may aggravate AD by promoting glycolysis. In addition, mechanism studies have shown that NORAD can exert VSMCs-regulating function by recruiting LIN28B to bind to TGF-β mRNA, which subsequently facilitates the expression of TGF-β1 (transforming growth factor β1). The recovery experiment also showed that overexpression of TGF-β could reverse the inhibitory effect of NORAD knockdown on VSMCs in terms of proliferation, migration, and glycolysis. Collectively, these results indicated that the NORAD/LIN28B/TGF-β axis promoted cell proliferation and migration through regulating aerobic glycolysis in VSMCs. Therefore, NORAD may regulate the occurrence of AD by affecting the reprogramming of glucose metabolism, and NORAD can be recognized as a good target for VSMC phenotypic intervention and AD treatment.

Micro RNA 200a contributes to the smooth muscle cells growth in aged-related erectile dysfunction via regulating Rho/ROCK pathway.

Aged-related erectile dysfunction (A-ED) is generally regarded as degeneration of penile erectile tissue due to age, male hormone deficiency and concomitant cardiovascular disease. Current pathological studies of A-ED are still limited. In this study, aged rats were divided into AE group (aged rats with ED) and YN group (young normal rats) for evaluating the roles of miRNA-200a and RhoA/ROCK signalling pathway in A-ED. Apo-morphine test, ICP measurement and pathological results were compared between these two groups. After transfection of miRNA-200a into Corpus cavernosum smooth muscle cells (CCSMCs), the expression of miRNA-200a, RhoA, ROCK1 and ROCK2 in the AE group were significantly increased. Additionally, miRNA-200a, RhoA, ROCK1 and ROCK2 were upregulated at a high level after transfecting the miRNA-200a mimics. Therefore, we speculated that miRNA-200a is a positive regulator, which may inhibit the growth of CCSMCs by activating the Rho/ROCK pathway in vitro.