Inducible Prmt1 ablation in adult vascular smooth muscle leads to contractile dysfunction and aortic dissection

Vascular smooth muscle cells (VSMCs) have remarkable plasticity in response to diverse environmental cues. Although these cells are versatile, chronic stress can trigger VSMC dysfunction, which ultimately leads to vascular diseases such as aortic aneurysm and atherosclerosis. Protein arginine methyltransferase 1 (Prmt1) is a major enzyme catalyzing asymmetric arginine dimethylation of proteins that are sources of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. Although a potential role of Prmt1 in vascular pathogenesis has been proposed, its role in vascular function has yet to be clarified. Here, we investigated the role and underlying mechanism of Prmt1 in vascular smooth muscle contractility and function. The expression of PRMT1 and contractile-related genes was significantly decreased in the aortas of elderly humans and patients with aortic aneurysms. Mice with VSMC-specific Prmt1 ablation (smKO) exhibited partial lethality, low blood pressure and aortic dilation. The Prmt1-ablated aortas showed aortic dissection with elastic fiber degeneration and cell death. Ex vivo and in vitro analyses indicated that Prmt1 ablation significantly decreased the contractility of the aorta and traction forces of VSMCs. Prmt1 ablation downregulated the expression of contractile genes such as myocardin while upregulating the expression of synthetic genes, thus causing the contractile to synthetic phenotypic switch of VSMCs. In addition, mechanistic studies demonstrated that Prmt1 directly regulates myocardin gene activation by modulating epigenetic histone modifications in the myocardin promoter region. Thus, our study demonstrates that VSMC Prmt1 is essential for vascular homeostasis and that its ablation causes aortic dilation/dissection through impaired myocardin expression.

The Impact of Monoclonal Antibodies on Airway Smooth Muscle Contractility in Asthma: A Systematic Review

Airway hyperresponsiveness (AHR) represents a central pathophysiological hallmark of asthma, with airway smooth muscle (ASM) being the effector tissue implicated in the onset of AHR. ASM also exerts pro-inflammatory and immunomodulatory actions, by secreting a wide range of cytokines and chemokines. In asthma pathogenesis, the overexpression of several type 2 inflammatory mediators including IgE, IL-4, IL-5, IL-13, and TSLP has been associated with ASM hyperreactivity, all of which can be targeted by humanized monoclonal antibodies (mAbs). Therefore, the aim of this review was to systematically assess evidence across the literature on mAbs for the treatment of asthma with respect to their impact on the ASM contractile tone. Omalizumab, mepolizumab, benralizumab, dupilumab, and tezepelumab were found to be effective in modulating the contractility of the ASM and preventing the AHR, but no available studies concerning the impact of reslizumab on the ASM were identified from the literature search. Omalizumab, dupilumab, and tezepelumab can directly modulate the ASM in asthma, by specifically blocking the interaction between IgE, IL-4, and TSLP, and their receptors are located on the surface of ASM cells. Conversely, mepolizumab and benralizumab have prevalently indirect impacts against AHR by targeting eosinophils and other immunomodulatory effector cells promoting inflammatory processes. AHR has been suggested as the main treatable trait towards precision medicine in patients suffering from eosinophilic asthma, therefore, well-designed head-to-head trials are needed to compare the efficacy of those mAbs that directly target ASM contractility specifically against the AHR in severe asthma, namely omalizumab, dupilumab, and tezepelumab.

VIP/PACAP Signaling as an Alternative Target During Hyperoxic Exposure in Preterm Newborns

The use of oxygen therapy (high doses of oxygen - hyperoxia) in the treatment of premature infants results in their survival. However, it also results in a high incidence of chronic lung disease known as bronchopulmonary dysplasia, a disease in which airway hyper-responsiveness and pulmonary hypertension are well known as consequences. In our previous studies, we have shown that hyperoxia causes airway hyper-reactivity, characterized by an increased constrictive and impaired airway smooth muscle relaxation due to a reduced release of relaxant molecules such as nitric oxide, measured under in vivo and in vitro conditions (extra- and intrapulmonary) airways. In addition, the relaxation pathway of the vasoactive intestinal peptide (VIP) and/or pituitary adenylate cyclase activating peptide (PACAP) is another part of this system that plays an important role in the airway caliber. Peptide, which activates VIP cyclase and pituitary adenylate cyclase, has prolonged airway smooth muscle activity. It has long been known that VIP inhibits airway smooth muscle cell proliferation in a mouse model of asthma, but there is no data about its role in the regulation of airway and tracheal smooth muscle contractility during hyperoxic exposure of preterm newborns.

Mechanism of Acitretin-Induced Relaxations in Isolated Rat Thoracic Aorta Preparations

Acitretin is a member of vitamin A-derived retinoids and its effect on vascular smooth muscle had not been studied yet. The aim of this study is to investigate the effect of acitretin, a retinoid, on vascular smooth muscle contractility. Thoracic aorta preparations obtained from 34 male Sprague-Dawley rats (355 ± 15 g) were studied in isolated organ baths containing Krebs-Henseleit solution. The relaxation responses were obtained with acitretin (10-12‒10-4 M) in endothelium-preserved and endothelium-denuded aorta preparations precontracted with submaximal concentration of phenylephrine. The roles of retinoic acid receptor (RAR), nitric oxide, adenylyl and guanylyl cyclase enzymes, and potassium channels in these relaxation responses were investigated. Acitretin produced concentration-dependent relaxations, which were independent of its solvent dimethylsulfoxide, in endothelium-denuded phenylephrine-precontracted thoracic aorta preparations. While incubation with the RAR antagonist (AGN193109, 10-5 M) had no effect on these relaxations; nitric oxide synthase inhibitor (L-NAME, 10-4 M), adenylyl cyclase inhibitor (SQ2253, 10-5 M), guanylyl cyclase inhibitor (ODQ, 10-6 M), and potassium channel blocker (tetraethylammonium-TEA, 10-2 M) significantly eliminated the relaxation responses induced by acitretin. Acitretin induces relaxation in rat isolated thoracic aorta preparations without endothelium, which may be mediated by nitric oxide, cyclic adenosine monophosphate and cyclic guanosine monophosphate-dependent kinases and potassium channels.

Role of Glucose-Lowering Medications in Erectile Dysfunction

Erectile dysfunction (ED) is a long-term complication of type 2 diabetes (T2D) widely known to affect the quality of life. Several aspects of altered metabolism in individuals with T2D may help to compromise the penile vasculature structure and functions, thus exacerbating the imbalance between smooth muscle contractility and relaxation. Among these, advanced glycation end-products and reactive oxygen species derived from a hyperglycaemic state are known to accelerate endothelial dysfunction by lowering nitric oxide bioavailability, the essential stimulus of relaxation. Although several studies have explained the pathogenetic mechanisms involved in the generation of erectile failure, few studies to date have described the efficacy of glucose-lowering medications in the restoration of normal sexual activity. Herein, we will present current knowledge about the main starters of the pathophysiology of diabetic ED and explore the role of different anti-diabetes therapies in the potential remission of ED, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting.

Management of Ineffective Esophageal Hypomotility

Esophageal hypomotility in general and especially ineffective esophageal motility according to the Chicago criteria of primary motility disorders of the esophagus, is one of the most frequently diagnosed motility disorders on high resolution manometry and results in a large number of patients visiting gastroenterologists. Most patients with esophageal hypomotility present with gastroesophageal reflux symptoms or dysphagia. The clinical relevance of the motility pattern, however, is not well established but seems to be correlated with disease severity in reflux patients. The correlation with dysphagia is less clear. Prokinetic agents are commonly prescribed as first line pharmacologic intervention to target esophageal smooth muscle contractility and improve esophageal motor functions. However, the beneficial effects of these medications are limited and only confined to some specific drugs. Serotonergic agents, including buspirone, mosapride and prucalopride have been shown to improve parameters of esophageal motility although the effect on symptoms is less clear. Understanding on the complex correlation between esophageal hypomotility and esophageal symptoms as well as the limited evidence of prokinetic agents is necessary for physicians to appropriately manage patients with Ineffective Esophageal Motility (IEM).

The underlying mechanisms of FGF2 on carotid atherosclerotic plaque development revealed by bioinformatics analysis

IntroductionThe purpose of this study was to explore the regulatory mechanisms of FGF2 on carotid atherosclerotic plaque development using bioinformatics analysis.Material and methodsExpression profiles of 32 atheroma plaque (AP) and 32 paired distant macroscopically intact (DMI) tissues samples in GSE43292 dataset were downloaded from the Gene Expression Omnibus database. Following identification of differential expression genes (DEGs), correlation analysis of fibroblast growth factor 2 (FGF2) and DEGs was conducted. Subsequently, functional enrichment analysis and protein-protein interaction network for FGF2 significantly correlated DEGs were constructed. Then, microRNAs (miRNAs) that regulated FGF2 and regulatory pairs of long noncoding RNA (lncRNA)-miRNA were predicted to construct lncRNA-miRNA-FGF2 network.ResultsA total of 101 DEGs between AP and DMI samples were identified, and 31 DEGs were analyzed to have coexpression relationships with FGF2, including 23 positively correlated and 8 negatively correlated DEGs. VAV3 had the lowest r value among all FGF2 negatively correlated DEGs. FGF2 positively correlated DEGs was closely related to “regulation of smooth muscle contraction” [eg., Calponin 1 (CNN1)], while FGF2 negatively correlated DEGs was significantly associated with “platelet activation” [eg., Vav Guanine Nucleotide Exchange Factor 3 (VAV3)]. In addition, totally 12 miRNAs that regulated FGF2 were predicted, and hsa-miR-15a-5p and hsa-miR-16-5p were highlighted in lncRNA-miRNA-FGF2 regulatory network.ConclusionsCNN1 might cooperate with FGF2 to regulate smooth muscle contractility during CAP formation. VAV3 might cooperate with FGF2 to be responsible for the development of CAP through participating in platelet activation. Hsa-miR-15a-5p and hsa-miR-16-5p might participate in the development of CAP via regulating FGF2.