Arterial Remodeling Research Articles

Association between premature vascular smooth muscle cells senescence and vascular inflammation in Takayasu’s arteritis

ObjectivesArterial wall inflammation and remodelling are the characteristic features of Takayasu’s arteritis (TAK). It has been proposed that vascular smooth muscle cells (VSMCs) are the main targeted cells of inflammatory...

Trophoblast cell-derived extracellular vesicles regulate the polarization of decidual macrophages by carrying miR-141-3p in the pathogenesis of preeclampsia

Dysregulation of macrophage polarization can prevent the invasion of trophoblast cells and further limit spiral artery remodeling in preeclampsia (PE). However, its mechanism is obscure. HTR8-/Svneo cells were cultured under normoxic or hypoxic conditions and extracellular vesicles (EVs) in the culture supernatants were extracted. Next, the cells were incubated with those EVs to investigate their effects on trophoblasts. A co-culture system consisting of HTR8-/Svneo cells and macrophages was used to reveal how the trophoblast-derived EVs affected the macrophage subtype. Finally, a PE mouse model and miR-141-3p knockout mice were used to verify the function of miR-141-3p in PE. Hypoxia induced abnormal increases in the levels of miR-141-3p in HTR8-/Svneo cells and EVs. EVs from hypoxia-treated HTR8-/Svneo cells could downregulate PTEN, a potential target of miR-141-3p, and inhibit trophoblast mitophagy and invasion. However, HTR8-/Svneo cells transfected with an miR-141-3p inhibitor could attenuate the influence of EVs. In an HTR8-/Svneo cell plus macrophage co-culture system, hypoxia-pretreated cells promoted the transformation of macrophages into the M1-phenotye, and HTR8-/Svneo invasion was inhibited by the macrophages. MiR-141 from EVs could target and downregulate dual specificity phosphatase 1 (DUSP1) expression in macrophages, induce formation of the M1 macrophage phenotype in THP-1 cells, downregulate DUSP1 expression, and upregulate TAB2/TAK1 signaling. These results were also demonstrated in normal pregnant mice and PE pregnant mice. A hypoxic environment could upregulate miR-141 expression in the EVs of HTR8-/Svneo cells, and THP-1-derived macrophages could uptake EVs releasing miR-141 to downregulate DUSP1 expression and induce the formation of M1 macrophages, which can lead to the development of PE.

The causes of pulmonary hypertension and the benefits of aerobic exercise for pulmonary hypertension from an integrated perspective.

Pulmonary hypertension is a progressive disease of the pulmonary arteries that begins with increased pulmonary artery pressure, driven by progressive remodeling of the small pulmonary arteries, and ultimately leads to right heart failure and death. Vascular remodeling is the main pathological feature of pulmonary hypertension, but treatments for pulmonary hypertension are lacking. Determining the process of vascular proliferation and dysfunction may be a way to decipher the pathogenesis of pulmonary hypertension. In this review, we summarize the important pathways of pulmonary hypertension pathogenesis. We show how these processes are integrated and emphasize the benign role of aerobic exercise, which, as an adjunctive therapy, may be able to modify vascular remodeling in pulmonary hypertension.

The Deubiquitinating Enzyme USP4 Promotes Trophoblast Dysfunction by Stabilizing RYBP.

Previous studies have suggested that impaired spiral artery remodeling, placental dysfunction, and insufficient trophoblast infiltration are the etiology and pathogenesis of Preeclampsia (PE). Ring 1 and YY1 binding protein (RYBP) has been reported to be associated with trophoblast dysfunction. However, the molecular mechanism of RYBP involved in trophoblasts in the pathogenesis of PE is poorly defined. RYBP and Ubiquitin-specific peptidase 4 (USP4) mRNA levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR). RYBP, USP4, p-PI3K, PI3K, p-AKT, and AKT protein levels were measured using western blot assay. Cell viability, proliferation, apoptosis, invasion, and migration were assessed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and wound healing assays. After ubibrowser database analysis, the interaction between USP4 and RYBP was verified using Co-immunoprecipitation (CoIP) assay. RYBP and USP4 expression were upregulated in placental tissues from PE patients. By using JEG-3 and HTR-8/SVneo trophoblast cells, RYBP overexpression or USP4 upregulation could hinder cell viability, proliferation, invasion, migration, and promote apoptosis. Mechanistically, USP4 could trigger the deubiquitination of RYBP and prevent its degradation. In addition, USP4 repressed the PI3K/AKT signaling pathway by regulating RYBP. In total, Decreased USP4-mediated ubiquitination results in an adverse impact on trophoblast function by enhancing RYBP expression, providing a novel therapeutic target for PE.

Superior cervical ganglionectomy attenuates vascular remodeling in spontaneously hypertensive rats.

Sympathetic hyperactivity contributes to the pathogenesis of hypertension. However, it is unclear whether the excessive sympathetic activity is an independent and crucial factor for vascular remodeling in hypertension. This study focused on the effect of local sympathetic denervation with superior cervical ganglionectomy (SCGx) on vascular remodeling. Surgical bilateral SCGx was performed in 9-week-old male Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Control rats received sham-operation without SCGx. All measurements were made 4 weeks after the surgery. The effectiveness of SCGx was confirmed by the eye features of Horner syndrome, greatly reduced tyrosine hydroxylase (TH) contents in the superior cervical ganglion (SCG)-innervated arteries in the head. Although SCGx had no significant effects on blood pressure and heart rate in WKY and SHR, it attenuated vascular remodeling of facial artery and superficial temporal artery in SHR, two representative SCG-innervated extracranial arteries, without significant effects on non-SCG-innervated thoracic aorta and mesenteric artery. SCGx-treated SHR had more auricular blood flow and retina microvasculature than sham-operated SHR. However, SCGx had only a mild effect in attenuating the vascular remodeling of basilar artery and middle cerebral artery, two representative SCG-innervated intracranial arteries, in SHR. SCGx-treated SHR exhibited upregulation of α-smooth muscle actin, downregulation of proliferating cell nuclear antigen, and attenuation of oxidative stress and inflammation in facial artery and superficial temporal artery. Sympathetic denervation by SCGx in SHR attenuated local vascular remodeling, suggesting that sympathetic overactivity is a crucial pathogenic factor of vascular remodeling in SHR.

MTOR in the Development of Hypoxic Pulmonary Hypertension Associated with Cardiometabolic Risk Factors.

The pathophysiology of pulmonary hypertension is complex and multifactorial. It is a disease characterized by increased pulmonary vascular resistance at the level due to sustained vasoconstriction and remodeling of the pulmonary arteries, which triggers an increase in the mean pulmonary artery pressure and subsequent right ventricular hypertrophy, which in some cases can cause right heart failure. Hypoxic pulmonary hypertension (HPH) is currently classified into Group 3 of the five different groups of pulmonary hypertensions, which are determined according to the cause of the disease. HPH mainly develops as a product of lung diseases, among the most prevalent causes of obstructive sleep apnea (OSA), chronic obstructive pulmonary disease (COPD), or hypobaric hypoxia due to exposure to high altitudes. Additionally, cardiometabolic risk factors converge on molecular mechanisms involving overactivation of the mammalian target of rapamycin (mTOR), which correspond to a central axis in the development of HPH. The aim of this review is to summarize the role of mTOR in the development of HPH associated with metabolic risk factors and its therapeutic alternatives, which will be discussed in this review.

The pH-sensing GPR68 and Rap1A: new kids in the arterial remodeling block.

The pH-sensing GPR68 and Rap1A: new kids in the arterial remodeling block.

DOCK1 deficiency drives placental trophoblast cell dysfunction by influencing inflammation and oxidative stress, hallmarks of preeclampsia.

Preeclampsia (PE) is a globally prevalent obstetric disorder, pathologically characterized by abnormal placental development. Dysfunctions of angiogenesis, vasculogenesis and spiral artery remodeling are demonstrated to be involved in PE pathogenesis; however, the underlying mechanisms remain largely unknown. Here, we investigated the role of the dedicator of cytokinesis 1 (DOCK1), crucial molecule in various cellular processes, in PE progression using HTR-8 cells derived from first-trimester placental extravillous trophoblasts. Our analysis revealed an aberrant DOCK1 expression in the placental villi of PE patients and its impact on essential cellular functions for vascular network formation. A deficiency of DOCK1 in HTR-8 cells impaired the vascular network formation, exacerbated the expression of anti-angiogenic factor ENG, and reduced VEGF levels. Moreover, DOCK1 knockout amplified apoptosis, as indicated by an altered BCL2: BAX ratio and enhanced levels of cleaved PARP. DOCK1 depletion also boosted NF-κB activation and pro-inflammatory cytokine production (IL-6 and TNF-α). Furthermore, the mice treated with DOCK1 inhibitor, TBOPP, exhibited PE-like symptoms. These findings highlight the multifaceted roles of DOCK1 in the pathophysiology of PE, demonstrating that its deficiency can lead to placental dysfunction by orchestrating inflammatory responses and oxidative stress. These insights emphasize the pathogenic role of DOCK1 in PE development and suggest potential treatment strategies that require further exploration. In the graphical abstract, a split image of placental villi contrasts the effects of normal and reduced DOCK1 expression on preeclampsia. The left side illustrates adequate DOCK1 levels supporting healthy trophoblast function and effective spiral artery remodeling. The right side highlights the consequences of DOCK1 deficiency, leading to trophoblast dysfunction and impaired spiral artery remodeling, accompanied by angiogenic imbalance, increased inflammation, oxidative stress, and apoptosis, contributing to placental dysfunction and the development of preeclampsia.

Maternal blood endometase level as a predictive biomarker for hypertensive disorders during pregnancy: a prospective cohort study

Preeclampsia (PE) occurs due to inadequate spiral artery/trophoblast remodeling in early pregnancy. Endometases are involved in the remodeling of spiral arteries and placental trophoblasts. This study aimed to investigate differences in blood endometase levels between pregnant women with hypertensive disorders (PE and gestational hypertension [GHT]) and healthy pregnant women and to evaluate whether plasma endometase values ​​could play a predictive role in PE or GHT diagnosis. A total of 90 pregnant women (n(PE) = 30, n(GHT) = 30, n(healthy pregnant) = 30) who presented at the hospital between December 2023 and May 2024 and were 26–32 years of age and > 20 weeks pregnant were included in the study. The endometase levels in all pregnant women were determined in maternal blood plasma via enzyme-linked immunosorbent assay. The endometase values were recalculated according to albumin values, and corrected endometase (cEndo) values were determined. No significant differences in blood endometase levels were observed between the groups (p > 0.05). The cEndo value was significantly lower in the PE and GHT groups than in the control group (p < 0.05). There was no statistically significant difference in the cEndo values between the PE and GHT groups (p > 0.05). A statistically significant negative linear relationship was detected between cEndo values and mean systolic blood pressure and mean diastolic blood pressure (p < 0.05). The cEndo values in the PE and GHT groups at early (≤ 32 weeks 3 days) and late pregnancy were compared, and no statistically significant difference was detected (p > 0.05). Maternal blood cEndo values may play a successful role in distinguishing hypertensive diseases of pregnancy (PE + GHT) from healthy pregnant women. cEndo does not play an effective role in the differential diagnosis between pregnant women with PE and those with GHT. Studies with larger patient populations are needed.

Pulmonary Vascular Disease in Chronic Obstructive Pulmonary Disease.

Pulmonary hypertension (PH) is a vascular disease characterized by pulmonary artery remodeling and right heart failure. PH related to COPD is a precapillary form of the disease, with hemodynamic measurements including a mean pulmonary artery pressure of greater than 20 mm Hg, a wedge pressure of less than 15 mm Hg, and a pulmonary vascular resistance of greater than 3 WU (Woods units), categorized under the World Health Organization classification as group 3. The presence of PH in COPD has been known to increase morbidity and mortality. Limited studies have evaluated treatment options for PH related to COPD.

Sinomenine Hydrochloride Regulates the Apoptosis of Endothelial Cells through PPAR-γ to Alleviate PAH.

Pulmonary arterial hypertension is a progressive heart and lung disease that is caused by irreversible pulmonary vascular remodeling. Sinomenine hydrochloride is an alkaloid that is extracted from sinomenium acutum, which has strong anti-inflammatory effects. In this study, male rats were injected with monocrotaline, and endothelial cells were exposed to hypoxia for 24 hours to induce pulmonary arterial hypertension. Apoptosis, inflammation, and oxidative stress pathways were observed the in lungs and cells. Sinomenine hydrochloride repressed the increased right ventricular systolic pressure and attenuated the right ventricular hypertrophy and pulmonary artery remodeling in model rats. It reversed the expression of BCL2 and BAX and prevented the apoptosis of endothelial cells. Additionally, it increased the contents of IKBα and NRF2. P65, P-P65, TNFα, IL1β, and IL6 levels in the lungs decreased by it. Malondialdehyde contents decreased, and the superoxide dismutase and glutathione peroxidase activity and HO-1 level increased in the treatment group. In vivo, it promoted apoptosis of pulmonary artery endothelial cells. Moreover, by activating PPAR-γ, sinomenine hydrochloride attains the above effects. These data suggested that sinomenine hydrochloride could protect endothelial cells, restrain inflammation and oxidative stress, and enhance pulmonary vascular remodeling.

Analysis of the results of optical coherence tomography to assess the effectiveness and safety of implantable bioresorbable stenting frames in the long term

Objective: to evaluate the effectiveness and safety of implantation of everolimus-coated bioabsorbable vascular scaffolds (BSCs) based on the results of optical coherence tomography (OCT) in patients with coronary artery disease who have previously undergone percutaneous coronary intervention (PCI). Materials and methods: OCT data from 23 patients with coronary artery disease (CAD) were studied 10 years or more after intervention with BVS implantation. Standard criteria based on OCT analysis were used to evaluate the efficacy of BVS. The stented segment, proximal zone before the stent, and distal zone after the stent were the areas of interest. Results: in the long-term period, the structure of the artery in the area of the installed biodegradable scaffolds is a combination of fragments of an atherosclerotic plaque, a resorbed scaffold, and neointima. When visualized using coherence tomography, this structure appears as a monolayer with high signal intensity. In 42.3% of patients, structures similar to fragments of the stenting frame were visualized, but smaller in size, with a disconnected structure, without clear contours and the absence of a typical shape. In 15.4% of cases, pronounced positive remodeling of the coronary artery in the area of the installation of the bioresorbable frame was noted. Conclusions: analysis of coherence tomography data showed that the use of biodegradable frames is effective and safe, the process of degradation of the frames occurs with an increase in diameter in the stented zone and the formation of a protective monolayer, while maintaining the patency of all side branches in the implantation zone.

The loss of dNK1/2 and EVT1 cells at the maternal-fetal Interface is associated with recurrent miscarriage

Abstract Recurrent miscarriage (RM) is a chronic and heterogeneous pregnancy disorder lacking effective treatment. Alterations at the maternal-fetal interface are commonly observed in RM, with the loss of certain cell subpopulations believed to be a key cause. Through single-cell sequencing of RM patients and healthy donors, we aim to identify aberrancy of cellular features in RM tissues, providing new insights into the research. Natural killer (NK) cells, the most abundant immune cells in the decidua, are traditionally classified into dNK1, dNK2, and dNK3. In this study, we identified a new subset, dNK1/2, absent in RM tissues. This subset was named because it expresses biomarkers of both dNK1 and dNK2. With further analysis, we discovered that dNK1/2 cells play roles in immunoregulation and cytokine secretion. On the villous side of the interface, a notable decrease of extravillous trophoblast (EVT) cells was identified in RM tissues. We clustered EVTs into EVT1 (absent in RM) and EVT2 (retained in RM). Pseudotime analysis revealed distinct differentiation paths, identifying CCNB1, HMGB1, and NPM1 as EVT1 biomarkers. Additionally, we found that EVT1 is involved in the regulation of cell death, while EVT2 exhibited more angiogenic activity. Cell communication analysis revealed that interaction between EVT1 and dNK1/2 mediates chemotaxis and endothelial cell regulation, crucial for spiral artery remodeling. The loss of this interaction may impair decidualization, which is associated with RM. In summary, we propose that the loss of dNK1/2 and EVT1 cells is a significant pathological feature of RM.

Follistatin lowers blood pressure and improves vascular structure and function in essential and secondary hypertension.

Hypertension is characterized by resistance artery remodeling driven by oxidative stress and fibrosis. We previously showed that an activin A antagonist, follistatin, inhibited renal oxidative stress and fibrosis in a model of hypertensive chronic kidney disease. Here, we investigate the effects of follistatin on blood pressure and vascular structure and function in models of essential and secondary hypertension. 5/6 nephrectomised mice, a model of secondary hypertension, were treated with either exogenous follistatin or with a follistatin miRNA inhibitor to increase endogenous follistatin for 9 weeks. Blood pressure in mice was measured by tail cuff. Spontaneously hypertensive rats, a model of essential hypertension, were treated with follistatin for 8 weeks. Wistar Kyoto (WKY) rats were used as the normotensive control. Blood pressure in rats was measured by radiotelemetry. Mouse superior mesenteric arteries and rat first branch mesenteric arteries were isolated for structural and functional analyses. In both models, follistatin significantly lowered blood pressure and improved vascular structure, decreasing medial thickness and collagen content. Follistatin also reduced agonist-induced maximum contraction and improved endothelium-dependent relaxation. Increased vessel oxidative stress was attenuated by follistatin in both models. In ex vivo WKY vessels, activin A increased oxidative stress, augmented constriction, and decreased endothelium-dependent relaxation. Inhibition of oxidative stress restored vessel relaxation. This study demonstrates that follistatin lowers blood pressure and improves vascular structure and function in models of essential and secondary hypertension. Effects were likely mediated through its inhibition of activin A and oxidative stress. These data suggest a potential therapeutic role for follistatin as a novel antihypertensive agent. Follistatin, through antagonization of activin A, inhibits oxidative stress and improves vascular structure and function in resistance arteries from models of essential and secondary HTN. FST decreases collagen content and vascular ROS. Functionally, FST improves endothelium-dependent relaxation and decreases maximal vasoconstriction. Improved resistance artery structure and function are correlated with a decrease in BP in both models.

Placental lesions in patients with antiphospholipid antibody syndrome: experience of a single tertiary-care Italian reference center

IntroductionAbnormal placentation contributes to obstetric morbidity in antiphospholipid antibodies syndrome (APS). The placenta is the main target of antiphospholipid antibodies (aPL) in obstetric APS and is the site of dysfunctional inflammatory responses and thrombosis. Standard treatment for APS during pregnancy includes low-dose aspirin (LDA) plus low molecular weight heparin (LMWH) and, in refractory cases, hydroxychloroquine (HCQ). Recently, a systematic review of the literature identified five main pathological placental lesions in APS patients: placental infarction, decidual vasculopathy, decidual inflammation, increase of syncytial knots due to syncytiotrophoblast death, and decrease in vasculosyncytial membranes. The aims of this study were to investigate whether placental lesions associate with obstetrical outcomes in a cohort of APS patients.Methods130 pregnant APS patients evaluated between 2009 and 2023 at the High-Risk Obstetrics Outpatient Clinic of San Raffaele Hospital, Milan, were enrolled. Placental samples from 25 spontaneously conceived pregnancies in APS patients were collected from January 2017 to May 2023 and analyzed.ResultsAll (n = 130) patients were on LDA and 110/130 (85%) on both LDA and LMWH. Twenty-six patients (20%) also received HCQ. In these patients, signs of placental inflammation (preterm birth and preterm premature rupture of membranes) were less frequently observed. Of the 25 placental samples analyzed, 19 (76%) patients had primary APS, while 6 patients had APS secondary to SLE. All patients were treated with LDA and LMWH. In patients with concomitant systemic lupus erythematosus (SLE) or in refractory APS, HCQ was added. Histological analysis of placental tissue revealed increased syncytial knots in 17/25 (68%) placentas, decreased vasculosyncytial membranes in 11/25 (44%), infarction in 8/25 (32%), presence of macrophages and decidual inflammation in 2/25 (8%), and atherosis or reduction of spiral artery remodeling in 3/25 (12%). We also observed at least two coexisting placental lesions in 12/25 (48%) placentas. In the placenta of patients treated with HCQ we did not observe any decidual inflammation at histology.ConclusionPlacental anomalies have occurred in patients with APS despite close and optimal obstetric monitoring. It is thus tempting to speculate that HCQ may have beneficial effects on pregnancy by decreasing the risk of deciduitis in patients with APS.

Mediative role of body mass index in cardiorespiratory fitness-associated vascular remodeling in youth.

Data on fitness-associated arterial remodeling in children is limited. We assessed the relation between cardiorespiratory fitness (CRF) and intima-media thickness (IMT), diameter, IMT:diameter-ratio (IDR), and tensile stress of the common carotid artery (CCA) in 697 healthy German schoolchildren. Further, we explored how body mass index (BMI) may influence these associations. We measured the vascular parameters with a high-resolution ultrasound device. We determined CRF using the FITNESSGRAM® PACER test and calculated each child's allometrically scaled peak oxygen uptake capacity (VO2peak). VO2peak, reflecting CRF, showed positive direct effects on IMT (girls: p < 0.001; boys: p = 0.02) and diameter in girls (p < 0.001). Considering BMI as a mediator, higher CRF was indirectly linked to decreases in IMT (girls: p = 0.04; boys: p = 0.02) and diameter (both p < 0.001), reflecting a competitive mediation. CRF indirectly mitigated the BMI-associated decrease in IDR (both p < 0.001) and increase in tensile stress (both p < 0.001) without affecting any of these parameters directly. CRF appears to be linked to uniform arterial remodeling with balanced hemodynamics and to further alleviate BMI-associated, potentially adverse vascular alterations, highlighting its significant role in cardiovascular health in youth. Data on CRF-associated arterial remodeling in youth is limited. Higher VO2peak, reflecting higher CRF, was positively associated with IMT in girls and boys and diameter in girls. These direct effects were counteracted by the indirect BMI-mediated effect of CRF on IMT and diameter, reflecting a competitive mediation. A higher CRF indirectly mitigated the BMI-associated decrease in IDR and increase in tensile stress without directly affecting any of these parameters. Our findings indicate homogenous remodeling and balanced hemodynamics with increasing CRF-and opposite effects with increasing BMI.

G6pdN126D Variant Increases the Risk of Developing VEGFR (Vascular Endothelial Growth Factor Receptor) Blocker-Induced Pulmonary Vascular Disease.

G6PD (glucose-6-phosphate-dehydrogenase) is a key enzyme in the glycolytic pathway and has been implicated in the pathogenesis of cancer and pulmonary hypertension-associated vascular remodeling. Here, we investigated the role of an X-linked G6pd mutation (N126D polymorphism), which is known to increase the risk of cardiovascular disease in individuals from sub-Saharan Africa and many others with African ancestry, in the pathogenesis of pulmonary hypertension induced by a vascular endothelial cell growth factor receptor blocker used for treating cancer. CRISPR-Cas9 genome editing was used to generate the G6pd variant (N126D; G6pdN126D) in rats. A single dose of the vascular endothelial cell growth factor receptor blocker sugen-5416 (SU; 20 mg/kg in DMSO), which is currently in a Phase 2/3 clinical trial for cancer treatment, was subcutaneously injected into G6pdN126D rats and their wild-type littermates. After 8 weeks of normoxic conditions, right ventricular pressure and hypertrophy, pulmonary artery remodeling, the metabolic profile, and cytokine expression were assessed. Right ventricular pressure and pulmonary arterial wall thickness were increased in G6PDN126D+SU/normoxic rats. Simultaneously, levels of oxidized glutathione, inositol triphosphate, and intracellular Ca2+ were increased in the lungs of G6PDN126D+SU/normoxic rats, whereas nitric oxide was decreased. Also increased in G6PDN126D+SU/normoxic rats were pulmonary levels of plasminogen activator inhibitor-1, thrombin-antithrombin complex, and expression of proinflammatory cytokines CCL3 (chemokine [C-C motif] ligand), CCL5, and CCL7. Our results suggest G6PDN126D increases inositol triphosphate-Ca2+ signaling, inflammation, thrombosis, and hypertrophic pulmonary artery remodeling in SU-treated rats. This suggests an increased risk of vascular endothelial cell growth factor receptor blocker-induced pulmonary hypertension in those carrying this G6PD variant.

Dysregulated Mitochondrial Calcium Causes Spiral Artery Remodeling Failure in Preeclampsia.

Calcium deficiency in women is strongly linked to an increased risk of developing preeclampsia. Mitochondrial calcium ([Ca2+]m) homeostasis is essential to regulate vascular smooth muscle cell (VSMC) function. However, the role of [Ca2+]m in preeclampsia development remains largely unknown. To investigate this, human spiral arteries obtained from normotensive and preeclamptic women were collected for vascular function, RNA sequencing, and VSMC studies. N(ω)-nitro-L-arginine methyl ester-induced preeclampsia animal experiments were established to investigate the effects of intervening in [Ca2+]m to improve the outcome for preeclamptic mothers or their infants. Our initial findings revealed compromised vessel function in spiral arteries derived from patients with preeclampsia, as evidenced by diminished vasoconstriction and vasodilation responses to angiotensin II and sodium nitroprusside, respectively. Moreover, the spiral artery VSMCs from patients with preeclampsia exhibited phenotypic transformation and proliferation associated with the disrupted regulatory mechanisms of [Ca2+]m uptake. Subsequent in vitro experiments employing gain- and loss-of-function approaches demonstrated that the mitochondrial Na+/Ca2+ exchanger played a role in promoting phenotypic switching and impaired mitochondrial functions in VSMCs. Furthermore, mtNCLX (mitochondrial Na+/Ca2+ exchanger) inhibitor CGP37157 significantly improved VSMC phenotypic changes and restored mitochondrial function in both patients with preeclampsia-derived VSMCs and the preeclampsia rat model. This study provides comprehensive evidence supporting the disrupted regulatory mechanisms of [Ca2+]m uptake in VSMCs of spiral arteries of patients with preeclampsia and further elucidates its correlation with VSMC phenotypic switching and defective spiral artery remodeling. The findings suggest that targeting mtNCLX holds promise as a novel therapeutic approach for managing preeclampsia.

Continuous infusion of resolvin D2 in combination with Angiotensin-II show contrary effects on blood pressure and intracardiac artery remodeling

Specialized pro-resolving mediators (SPMs) are key effectors of resolution of inflammation. This is highly relevant for cardiac and vessel remodeling, where the net inflammatory response contributes to determine disease outcome. Herein, we used a mice model of angiotensin (Ang)–II–induced hypertension to study the effect of the SPM Resolvin D2 (RvD2), on hypertension and cardiac remodeling. By using subcutaneous osmotic minipumps, mice were treated with PBS or Ang-II in combination with or without RvD2 for two weeks. Mice receiving RvD2 gained less blood pressure increase compared to Ang-II alone. Surprisingly, however, examination of intracardiac arteries revealed that RvD2 treatment in combination with Ang-II exacerbated Ang–II–induced fibrosis. Measures of vascular smooth muscle cell dedifferentiation correlated with the level of vascular remodeling, indicating that this dedifferentiation, including increased proliferation and migration, is a contributing factor. RNA sequencing of left ventricle cardiac tissue supported these findings as pathways related to cell proliferation and cell differentiation were upregulated in mice treated with Ang-II in combination with RvD2. Additionally, the RNA sequencing also showed upregulation of pathways related to SPM metabolism. In line with this, Mass spectrometry analysis of lipid mediators showed reduced cardiac levels of the arachidonic acid derived metabolite leukotriene E4 in RvD2 treated mice. Our study suggests that continuous infusion through osmotic minipumps should not be the recommended route of RvD2 administration in future studies.

Empagliflozin Attenuates Pulmonary Arterial Remodeling Through Peroxisome Proliferator-Activated Receptor Gamma Activation.

The loss of peroxisome proliferator-activated receptor gamma (PPARγ) exacerbates pulmonary arterial hypertension (PAH), while its upregulation reduces cell proliferation and vascular remodeling, thereby decreasing PAH severity. SGLT2 inhibitors, developed for type 2 diabetes, might also affect signal transduction in addition to modulating sodium-glucose cotransporters. Pulmonary arterial smooth muscle cells (PASMCs) isolated from patients with idiopathic pulmonary arterial hypertension (IPAH) were treated with three SGLT2 inhibitors, canagliflozin (Cana), dapagliflozin (Dapa), and empagliflozin (Empa), to investigate their antiproliferative effects. To assess the impact of Empa on PPARγ, luciferase reporter assays and siRNA-mediated PPARγ knockdown were employed to examine regulation of the γ-secretase complex and its downstream target Notch3. Therapy involving daily administration of Empa was initiated 21 days after inducing hypoxia-induced PAH in mice. Empa exhibited significant antiproliferative effects on fast-growing IPAH PASMCs. Empa activated PPARγ to prevent formation of the γ-secretase complex, with specific impacts on presenilin enhancer 2 (PEN2), which plays a crucial role in maintaining γ-secretase complex stability, thereby inhibiting Notch3. Similar results were obtained in lung tissue of chronically hypoxic mice. Empa attenuated pulmonary arterial remodeling and right ventricle hypertrophy in a hypoxic PAH mouse model. Moreover, PPARγ expression was significantly decreased and PEN2, and Notch3 levels were increased in lung tissue from PAH patients compared with non-PAH lung tissue. Empa reverses vascular remodeling by activating PPARγ to suppress the γ-secretase-Notch3 axis. We propose Empa as a PPARγ activator and potential therapeutic for PAH.