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The use of human pluripotent stem cells for in vitro disease modelling and clinical applications requires protocols that convert these cells into relevant adult cell types. Here, we report the rapid and efficient differentiation of human pluripotent stem cells into vascular endothelial and smooth muscle cells. We found that GSK3 inhibition and BMP4 treatment rapidly committed pluripotent cells to a mesodermal fate and subsequent exposure to VEGF-A or PDGF-BB resulted in the differentiation of either endothelial or vascular smooth muscle cells, respectively. Both protocols produced mature cells with efficiencies exceeding 80% within six days. On purification to 99% via surface markers, endothelial cells maintained their identity, as assessed by marker gene expression, and showed relevant in vitro and in vivo functionality. Global transcriptional and metabolomic analyses confirmed that the cells closely resembled their in vivo counterparts. Our results suggest that these cells could be used to faithfully model human disease. Cowan and colleagues report a method to generate mature endothelial or vascular smooth muscle cells from human pluripotent stem cells with high efficiency and purity.

In this work we study strong spectral properties of Ruelle transfer operators related to a large family of Gibbs measures for contact Anosov flows. The ultimate aim is to establish exponential decay of correlations for Hölder observables with respect to a very general class of Gibbs measures. The approach invented in 1997 by Dolgopyat in “On decay of correlations in Anosov flows” and further developed in Stoyanov (2011) is substantially refined here, allowing to deal with much more general situations than before, although we still restrict ourselves to the uniformly hyperbolic case. A rather general procedure is established which produces the desired estimates whenever the Gibbs measure admits a Pesin set with exponentially small tails, that is a Pesin set whose preimages along the flow have measures decaying exponentially fast. We call such Gibbs measures regular. Recent results in Gouëzel and Stoyanov (2019) prove existence of such Pesin sets for hyperbolic diffeomorphisms and flows for a large variety of Gibbs measures determined by Hölder continuous potentials. The strong spectral estimates for Ruelle operators and well-established techniques lead to exponential decay of correlations for Hölder continuous observables, as well as to some other consequences such as: (a) existence of a non-zero analytic continuation of the Ruelle zeta function with a pole at the entropy in a vertical strip containing the entropy in its interior; (b) a Prime Orbit Theorem with an exponentially small error.

Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.

The pathobiology of atherosclerotic disease requires further elucidation to discover new approaches to address its high morbidity and mortality. To date, over 17 million cardiovascular-related deaths have been reported annually, despite a multitude of surgical and nonsurgical interventions and advances in medical therapy. Existing strategies to prevent disease progression mainly focus on management of risk factors, such as hypercholesterolemia. Even with optimum current medical therapy, recurrent cardiovascular events are not uncommon in patients with atherosclerosis, and their incidence can reach 10–15% per year. Although treatments targeting inflammation are under investigation and continue to evolve, clinical breakthroughs are possible only if we deepen our understanding of vessel wall pathobiology. Vascular smooth muscle cells (VSMCs) are one of the most abundant cells in vessel walls and have emerged as key players in disease progression. New technologies, including in situ hybridization proximity ligation assays, in vivo cell fate tracing with the CreER T2 -loxP system and single-cell sequencing technology with spatial resolution, broaden our understanding of the complex biology of these intriguing cells. Our knowledge of contractile and synthetic VSMC phenotype switching has expanded to include macrophage-like and even osteoblast-like VSMC phenotypes. An increasing body of data suggests that VSMCs have remarkable plasticity and play a key role in cell-to-cell crosstalk with endothelial cells and immune cells during the complex process of inflammation. These are cells that sense, interact with and influence the behavior of other cellular components of the vessel wall. It is now more obvious that VSMC plasticity and the ability to perform nonprofessional phagocytic functions are key phenomena maintaining the inflammatory state and senescent condition and actively interacting with different immune competent cells.

Reactive oxygen species (ROS) are natural byproducts of oxygen metabolism in the cell. At physiological levels, they play a vital role in cell signaling. However, high ROS levels cause oxidative stress, which is implicated in cardiovascular diseases (CVD) such as atherosclerosis, hypertension, and restenosis after angioplasty. Despite the great amount of research conducted to identify the role of ROS in CVD, the image is still far from being complete. A common event in CVD pathophysiology is the switch of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype. Interestingly, oxidative stress is a major contributor to this phenotypic switch. In this review, we focus on the effect of ROS on the hallmarks of VSMC phenotypic switch, particularly proliferation and migration. In addition, we speculate on the underlying molecular mechanisms of these cellular events. Along these lines, the impact of ROS on the expression of contractile markers of VSMCs is discussed in depth. We conclude by commenting on the efficiency of antioxidants as CVD therapies.

Evogliptin, an anti-diabetic drug had positive impact on various cardiovascular events including inflammation and vascular calcification (VC), an active process driven by vascular smooth muscle cell (VSMC) phenotypic transition. Sphingolipids such as ceramide (CER) mediates inflammation and VC in the vascular tissue. We investigated whether evogliptin ameliorate phenotypic transition and pyroptosis in VSMCs as underlying cause of VC. In cultured VSMCs, isolated from the aorta of (C57/BL6) mouse, we observed more severe calcification with prior treatment of CER in Pi-treated VSMCs as detected by Alizarin Red Staining. Prior CER- stimulation led to a marked upregulation of osteogenic markers such as RUNX2, OPN, BMP2 and decreased contractile markers SM22-α and α- SMA in Pi-treated VSMCs as compared to control cells. In addition, increased expression of pyroptotic markers such as NLRP3, GSDM-D, IL-1β, IL-18, and LDH release was observed with prior treatment of CER in Pi-treated VSMCs as compared to control cells. Furthermore, MCC950 (NLRP3 inhibitor), disulfiram (GSDM-D inhibitor) and evogliptin significantly downregulated osteogenic and pyroptotic markers including LDH release in both Pi-induced only and CER + Pi-treated VSMCs. Moreover, GW4869 (SMase inhibitor) and evogliptin significantly reduced SMase activity in sphingomyelin (SM)-induced VSMCs as compared to both Pi and SM only-treated groups. Also, the cleavage efficiency of GSDM-D was high in Pi and CER + Pi groups which was reduced with prior treatment of evogliptin. Hence, our data demonstrate that evogliptin alleviates VC by blocking phenotypic transition and associated pyroptosis via modulation of NLRP3/GSDM-D mediated pathway in CER-induced VSMCs.

Background Nitrogen-containing bisphosphonate(N-BP)had been found to inhibit the osteogenic differentiation and calcification in vascular smooth muscle cells (VSMCs), but the mechanism is not clear. We intend to verify that N-BP induces enhancement of OPG expression and inhibition of RANKL expression via inhibition of farnesyl pyrophosphate synthase(FPPS) to inhibit the osteogenic differentiation and calcification in VSMCs. Methods β-glycerophosphate (β-GP) was used to induce the osteogenic differentiation and calcification in VSMCs. VSMCs were treated with N-BP or pretreated with downstream products of farnesyl pyrophosphate synthase(FPPS) in mevalonate pathway, such as farnesol (FOH) or geranylgeraniol (GGOH). Alizarin red S staining and determination of calcium content were used to detect calcium deposition.Western Blotting were used to detect expressions of proteins(OPG and RANKL ) and osteogenic marker proteins (Runx2 and OPN). Results β-GP induced the osteogenic differentiation and calcification in VSMCs, increased RANKL protein expression and had no significant effect on OPG protein expression. With the treatment of N-BP, the expression of OPG protein was increased and expression of RANKL protein was decreased in VSMCs undergoing osteogenic differentiation and calcification. In addition, N-BP reduced the osteogenic marker proteins (Runx2 and OPN) expression and calcium deposition in VSMCs undergoing osteogenic differentiation and calcification. These effects of N-BP on the osteogenic differentiation and calcification in VSMCs were concentration-dependent, which could be reversed by the downstream products of FPPS, such as FOH or GGOH. Conclusion N-BP increases OPG expression and decreases RANKL expression via inhibition of FPPS to inhibit the osteogenic differentiation and calcification in VSMCs.

Microplastics (MPs) are an emerging environmental issue due to their accumulation in ecosystems and living organisms. Increasing evidence shows that MPs impact vascular function, with recent studies finding MPs in atheromas linked to cardiovascular events. Since vascular smooth muscle cells (VSMCs) are crucial to maintaining vascular function, this study examined how MPs activate VSMCs, leading to cardiovascular diseases like atherosclerosis and vascular calcification. The study used polyethylene (PE) and polystyrene (PS), common in food packaging, as “virgin” or photo-degraded to simulate environmental conditions. VSMC viability, apoptosis, cytotoxicity, inflammation, and activation markers were evaluated. PE and PS affected VSMC viability, induced apoptosis, and triggered pathological changes such as altered migration and proliferation. Key markers like RUNX-2 and galectin-3, which regulate cardiovascular pathology, were activated, alongside the inflammasome complex. In conclusion, MPs can induce harmful activation of VSMCs, posing potential health risks through inflammation, cell damage, and phenotypic changes. Understanding these toxic mechanisms may reveal critical pathways for intervention and prevention.

Current asthma therapies fail to target airway remodeling that correlates with asthma severity driving disease progression that ultimately leads to loss of lung function. Macroautophagy (hereinafter “autophagy”) is a fundamental cell-recycling mechanism in all eukaryotic cells; emerging evidence suggests that it is dysregulated in asthma. We investigated the interrelationship between autophagy and airway remodeling and assessed preclinical efficacy of a known autophagy inhibitor in murine models of asthma. Human asthmatic and nonasthmatic lung tissues were histologically evaluated and were immunostained for key autophagy markers. The percentage area of positive staining was quantified in the epithelium and airway smooth muscle bundles using ImageJ software. Furthermore, the autophagy inhibitor chloroquine was tested intranasally in prophylactic (3 wk) and treatment (5 wk) models of allergic asthma in mice. Human asthmatic tissues showed greater tissue inflammation and demonstrated hallmark features of airway remodeling, displaying thickened epithelium (P < 0.001) and reticular basement membrane (P < 0.0001), greater lamina propria depth (P < 0.005), and increased airway smooth muscle bundles (P < 0.001) with higher expression of Beclin-1 (P < 0.01) and ATG5 (autophagy-related gene 5) (P < 0.05) together with reduced p62 (P < 0.05) compared with nonasthmatic control tissues. Beclin-1 expression was significantly higher in asthmatic epithelium and ciliated cells (P < 0.05), suggesting a potential role of ciliophagy in asthma. Murine asthma models demonstrated effective preclinical efficacy (reduced key features of allergic asthma: airway inflammation, airway hyperresponsiveness, and airway remodeling) of the autophagy inhibitor chloroquine. Our data demonstrate cell context–dependent and selective activation of autophagy in structural cells in asthma. Furthermore, this pathway can be effectively targeted to ameliorate airway remodeling in asthma.

Vascular smooth muscle cells (VSMCs) are the most abundant cell type in blood vessels, participating in cardiovascular diseases in various ways, among which their transformation into macrophage-like cells has become a research hotspot. In this study, rats were infused with aldosterone for 12 weeks, and VSMCs stimulated with aldosterone in vitro were used to observe aortic injury and the role of VSMC transformation. Vascular changes were detected via small animal ultrasound and H&E staining. Moreover, immunohistochemistry, immunofluorescence, Western blot, and flow cytometry were used to verify that the transformation of VSMCs into macrophage-like cells is regulated by mineralocorticoid receptor (MR) activation and macrophage colony-stimulating factor (M-CSF) and its receptor. Rat vasculature and in vitro cellular experiments revealed that VSMCs transformed into macrophage-like cells and secreted inflammatory factors such as interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1), thereby exacerbating inflammatory vascular lesions, which was inhibited by the MR antagonist esaxerenone. These results reveal that increased levels of aldosterone activate MR, leading to the secretion of M-CSF by VSMCs. This further promotes the transformation of VSMCs into macrophage-like cells, which participate in inflammatory vascular lesions. Therefore, inhibiting the formation of macrophage-like cells can effectively reduce inflammatory vascular lesions.