Arterial Remodeling Research Articles

Renal denervation restores biomechanics of carotid arteries in a rat model of hypertension

The prevalence of hypertension increases with aging and is associated with increased arterial stiffness. Resistant hypertension is presented when drug treatments fail to regulate a sustained increased blood pressure. Given that the mechanisms between the sympathetic nervous system and the kidney play an important role in blood regulation, renal denervation (RDN) has emerged as a therapeutic potential in resistant hypertension. In this study, we investigated the effects of RDN on the biomechanical response and microstructure of elastic arteries. Common carotid arteries (CCA) excised from 3-month, 8-month, and 8-month denervated rats were subjected to biaxial extension-inflation test. Our results showed that hypertension developed in the 8-month-old rats. The sustained elevated blood pressure resulted in arterial remodeling which was manifested as a significant stress increase in both axial and circumferential directions after 8 months. RDN had a favorable impact on CCAs with a restoration of stresses in values similar to control arteries at 3 months. After biomechanical testing, arteries were imaged under a multi-photon microscope to identify microstructural changes in extracellular matrix (ECM). Quantification of multi-photon images showed no significant alterations of the main ECM components, elastic and collagen fibers, indicating that arteries remained intact after RDN. Regardless of the experimental group, our microstructural analysis of the multi-photon images revealed that reorientation of the collagen fibers might be the main microstructural mechanism taking place during pressurization with their straightening happening during axial stretching.

Aldehyde Dehydrogenase 2 (ALDH2) rs671 Polymorphism is a Predictor of Pulmonary Hypertension Due to Left Heart Disease

Pulmonary hypertension due to left heart disease (PH-LHD) is commonly seen in patients with heart failure (HF), but there are limited treatment options. Recent studies have shown an association between aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphisms and pulmonary hypertension (PH). Therefore, this study aimed to investigate the occurrence of ALDH2 rs671 polymorphisms, and the association between ALDH2 and risk of PH-LHD in patients with HF. It also investigated different ALDH2 genotypes and examined their association with cardiac structure and function in HF patients with PH-LHD. A total of 178 HF patients were consecutively enrolled in this study: 102 without PH-LHD and 76 with PH-LHD. Clinical data, parameters of echocardiography, and relevant biochemical indexes were recorded in both groups. Differences in data obtained between groups were compared, and the risk of variant ALDH2 polymorphisms with PH-LHD in HF patients was analysed using univariate and multivariate logistic regression. The prevalence of ALDH2 rs671 GA/AA polymorphisms (variant ALDH2) was 24 of 102 patients (23.53%) in the HF without PH-LHD group, and 32 of 76 patients (42.10%) in the HF with PH-LHD group, with a statistically significant difference. Univariate and multivariate logistical regression showed that variant ALDH2 is an independent risk factor for HF combined with PH-LHD. A higher proportion of patients with variant ALDH2 in the HF with PH-LHD group had a tricuspid regurgitation velocity >2.8 m/s, and they had higher values of peak early diastolic velocity of the mitral orifice/peak velocity of the early diastolic wave of the mitral orifice, maximum frequency shift of pulmonary valve flow, and pulmonary artery stiffness. Variant ALDH2 may be an independent risk factor for HF combined with PH-LHD. Variant ALDH2 may also be involved in pulmonary artery remodelling and is a potential new target for clinical treatment of PH-LHD.

Cellular senescence in the pathogenesis of pulmonary arterial hypertension: the good, the bad and the uncertain.

Senescence refers to a cellular state marked by irreversible cell cycle arrest and the secretion of pro-inflammatory and tissue-remodeling factors. The senescence associated secretory phenotype (SASP) impacts the tissue microenvironment and provides cues for the immune system to eliminate senescent cells (SCs). Cellular senescence has a dual nature; it can be beneficial during embryonic development, tissue repair, and tumor suppression, but it can also be detrimental in the context of chronic stress, persistent tissue injury, together with an impairment in SC clearance. Recently, the accumulation of SCs has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH), a progressive condition affecting the pre-capillary pulmonary arterial bed. PAH is characterized by endothelial cell (EC) injury, inflammation, and proliferative arterial remodeling, which leads to right heart failure and premature mortality. While vasodilator therapies can improve symptoms, there are currently no approved treatments capable of reversing the obliterative arterial remodeling. Ongoing endothelial injury and dysfunction is central to the development of PAH, perpetuated by hemodynamic perturbation leading to pathological intimal shear stress. The precise role of senescent ECs in PAH remains unclear. Cellular senescence may facilitate endothelial repair, particularly in the early stages of disease. However, in more advanced disease the accumulation of senescent ECs may promote vascular inflammation and occlusive arterial remodeling. In this review, we will examine the evidence that supports a role of endothelial cell senescence to the pathogenesis of PAH. Furthermore, we will compare and discuss the apparent contradictory outcomes with the use of interventions targeting cellular senescence in the context of experimental models of pulmonary hypertension. Finally, we will attempt to propose a framework for the understanding of the complex interplay between EC injury, senescence, inflammation and arterial remodeling, which can guide further research in this area and the development of effective therapeutic strategies.

Biomechanical factors and atherosclerosis localization: insights and clinical applications.

Although the entire vascular bed is constantly exposed to the same risk factors, atherosclerosis manifests a distinct intra-individual pattern in localization and progression within the arterial vascular bed. Despite shared risk factors, the development of atherosclerotic plaques is influenced by physical principles, anatomic variations, metabolic functions, and genetic pathways. Biomechanical factors, particularly wall shear stress (WSS), play a crucial role in atherosclerosis and both low and high WSS are associated with plaque progression and heightened vulnerability. Low and oscillatory WSS contribute to plaque growth and arterial remodeling, while high WSS promotes vulnerable changes in obstructive coronary plaques. Axial plaque stress and plaque structural stress are proposed as biomechanical indicators of plaque vulnerability, representing hemodynamic stress on stenotic lesions and localized stress within growing plaques, respectively. Advancements in imaging and computational fluid dynamics techniques enable a comprehensive analysis of morphological and hemodynamic properties of atherosclerotic lesions and their role in plaque localization, evolution, and vulnerability. Understanding the impact of mechanical forces on blood vessels holds the potential for developing shear-regulated drugs, improving diagnostics, and informing clinical decision-making in coronary atherosclerosis management. Additionally, Computation Fluid Dynamic (CFD) finds clinical applications in comprehending stent-vessel dynamics, complexities of coronary bifurcations, and guiding assessments of coronary lesion severity. This review underscores the clinical significance of an integrated approach, concentrating on systemic, hemodynamic, and biomechanical factors in atherosclerosis and plaque vulnerability among patients with coronary artery disease.

Abnormal miR-122-5p expression in decidual NK cells and its impact on trophoblast behavior: insights into unexplained recurrent pregnancy loss.

In the early stages of pregnancy, the maternal-fetal interface is enriched with natural killer (NK) cells that release growth factors to support fetal development and promote the remodeling of uterine spiral arteries. Previous studies have shown that the aberrant frequency and activity of decidual natural killer (dNK) cells are associated with recurrent pregnancy loss (RPL). Various factors regulate the roles of dNK cells and their interactions with trophoblasts to facilitate the colonization and maturation of semiallogeneic embryos. However, knowing precise molecular mechanisms involved in this requires further investigation. Earlier studies revealed that microRNAs (miRNAs) play a significant role in regulating the functions of decidual stromal and trophoblast cells. Although there are few studies on the intervention of malfunctioning dNK cells, this strategy shows promise in regulating abnormal miRNA production in NK cells. This study confirmed miR-122-5p downregulation in dNK cells from patients experiencing unexplained RPL. miR-122-5p regulates apoptosis, inflammatory factor secretion, and cytotoxicity of NK cells. miR-122-5p may contribute to immune tolerance at the maternal-fetal interface by targeting transcription factor T-bet. This study provides a deeper understanding of the mechanisms by which miR-122-5p regulates the function of dNK cells and trophoblasts at the maternal-fetal interface to ensure successful pregnancy.

Unilateral Lung Removal in Combination with Monocrotaline or SU5416 in Rodents: A Reliable Model to Mimic the Pathology of the Human Pulmonary Hypertension.

Pulmonary hypertension (PH) is a chronic and progressive disorder characterized by elevated mean pulmonary arterial pressure, pulmonary vascular remodeling, and the development of concentric laminar intimal fibrosis with plexiform lesions. While rodent models have been developed to study PH, they have certain deficiencies and do not entirely replicate the human disease due to the heterogeneity of PH pathology. Therefore, combined models are necessary to study PH. Recent studies have shown that altered pulmonary blood flow is a significant trigger in the development of vascular remodeling and neointimal lesions. One of the most promising rodent models for increased pulmonary flow is the combination of unilateral left pneumonectomy with a "second hit" of monocrotaline (MCT) or SU5416. The removal of one lung in this model forces blood to circulate only in the other lung and induces increased and turbulent pulmonary blood flow. This increased vascular flow leads to progressive remodeling and occlusion of small pulmonary arteries. The second hit by MCT or SU5416 leads to endothelial cell dysfunction, resulting in severe PH and the development of plexiform arteriopathy.

Expression of sirtuins 1 in placenta, umbilical cord, and maternal serum of patients diagnosed with placenta accreta spectrum.

Placenta accreta spectrum (PAS) is defined as the attachment of the placenta to the uterine wall in varying degrees. However, the studies have explored that the underlying molecular mechanisms of the PAS are very limited. Sirtuins 1 (SIRT1) is associated with placental development by controlling trophoblast cell invasion and remodeling of spiral arteries. We aimed to determine the expression level of SIRT1 in placentas, and maternal and umbilical cord serum of patients with PAS. In total, 30 individuals in control, 20 patients in the placenta previa group, and 30 patients in the PAS group were included in this study. The expression levels of SIRT1 in the placentas were determined by Western blot and immunohistochemistry. Serum levels of SIRT1 in maternal and umbilical cord blood were determined by ELISA. SIRT1 was significantly lower in placentas of the PAS. However, maternal and umbilical cord serum samples were not significantly different between groups. SIRT1 may play an important role in the pathogenesis of the PAS.

Changes in the indicators of stiffness and remodeling of magistral arteries in young patients at the early stage of essential hypertension under conditions of syntropy with obesity.

Aim: The study and analysis of indicators of remodeling and rigidity of magistral vessels in young essential hypertension patients with abdominal obesity and determination of the detected changes as a possible criterion for their remodeling.. Materials and Methods: 98 young people with essential hypertension and obesity were included in the study. The structure of the carotid artery and its stiffness were assessed using the ultrasound method, and the level of abdominal fat was determined using dual-energy X-ray absorptiometry. Results: Carotid Intima-Media Thickness in patients with essential hypertension reliably exceeded the corresponding indicator of the control group. We observed a significant increase in arterial stiffness indicators, which is explained by the increased stiffness of blood vessels in patients with obesity. During the correlation analysis, it was established that the relationship between the level of abdominal fat and the elasticity of the vascular wall was positive and strong, which indicated the dominant role of the abdominal type of obesity in the remodeling of the vascular wall in young patients with essential hypertension in combination with obesity. Conclusions: In young patients at the early stage of the formation of essential hypertension, there are signs of a decrease in resilient-elastic properties and remodeling of magistral vessels, whose severity is significantly stronger in combination with abdominal obesity.

Морфологические особенности эндометрия у пациенток с ожирением и ранними репродуктивными потерями

Aim. To clarify and summarize current data on the relationship between morphological features of gravid transformation of the endometrium and early reproductive losses in women with obesity. Key points. The growing prevalence of obesity worldwide is of serious concern not only due to numerous metabolic complications associated with excess visceral adipose tissue, but also due to reproductive dysfunction in women. Obesity is considered a key factor that increases several times the likelihood of pregnancy complications such as spontaneous abortion, non-viable pregnancy, stillbirth, gestational diabetes mellitus, and preeclampsia. The development of adverse events in the context of maternal obesity may be based on the interaction of biological processes associated with pregnancy and chronic inflammation caused by obesity. However, the causal relationship between BMI and spontaneous abortion is not fully understood, possibly due to the multifactorial effects of excess body weight on pregnancy progression. In addition, BMI as an isolated variable may not reflect other important health risk factors such as nutrition, physical activity, and insulin resistance. Conclusion. Female obesity is associated with worse natural and assisted conception outcomes, including an increased risk of spontaneous abortion. Low-grade inflammation affecting arterial remodeling, placentation, and uterine immune cell composition and activity in maternal obesity contributes to a high incidence of pregnancy complications. The development of a unified morphological panel that takes into account the main indicators of endometrial transformation processes with an assessment of its receptor profile and diagnostically significant immunological factors will allow verification of endometrial pathology at the molecular level and justification of pathogenetic therapy in the risk group of early reproductive losses in women with obesity. Keywords: gravid endometrium, obesity, reproductive function, reproductive losses, miscarriage.

Indigo Leaves-Induced Pulmonary Arterial Remodeling without Right Ventricular Hypertrophy in Rats.

Indigo naturalis (IN), derived from the leaves of the indigo plant, is a traditional Chinese medicine that has historically been used for its anti-inflammatory properties in the treatment of various diseases, including ulcerative colitis (UC). However, long-term use of IN in UC patients is incontrovertibly associated with the onset of pulmonary arterial hypertension (PAH). To investigate the mechanisms by which IN induces PAH, we focused on the raw material of IN, indigo leaves (IL). Only the condition of long-term chronic (6 months) and high-dose (containing 5% IL in the control diet) administration of IL induced medial thickening in the pulmonary arteries without right ventricular hypertrophy in our rat model. IL administration for a month did not induce pulmonary arterial remodeling but increased endothelin-1 (ET-1) expression levels within endothelial cell (EC) layers in the lungs. Gene Expression Omnibus analysis showed that ET-1 is a key regulator of PAH and that the IL component indican and its metabolite IS induced ET-1 mRNA expression via reactive oxygen species-dependent mechanism. We identified the roles of indican and IS in ET-1 expression in ECs, which were linked to pulmonary arterial remodeling in an animal model.

Echinacoside inhibits PASMCs calcium overload to prevent hypoxic pulmonary artery remodeling by regulating TRPC1/4/6 and calmodulin.

Research indicates that hypoxic pulmonary hypertension (HPH) potentially stimulates the sympathetic nervous system, which may increase norepinephrine (NE) release and cause excessive Ca2+ influx into pulmonary artery smooth muscle cells (PASMCs), leading to calcium overload and abnormal PASMC proliferation, factors closely associated with pulmonary vascular remodeling (PVR). This study investigates the potential mechanisms underlying echinacoside (ECH) treatment in HPH. In the in vitro experiment, NE-induced PASMCs were used to simulate HPH-induced PASMCs' calcium overload and abnormal proliferation. Postincubation with ECH, [Ca2+]cyt changes were detected using Fluo-4 AM. Flow cytometry was employed to ascertain ECH's inhibitory effect on PASMCs proliferation. For in vivo experiments, rats were exposed to a hypoxic and low-pressure oxygen environment to establish the HPH model. Post-ECH treatment, hematoxylin and eosin (HE) staining was conducted to assess PVR, and western blot analysis was used to examine protein expression in the lung tissues of the different groups. ECH was observed to inhibit [Ca2+]cyt increase in NE-induced PASMCs in a concentration-dependent manner, effectively reducing abnormal cell proliferation. It also reduced the expression of Transient receptor potential channel (TRPC) 1 (TRPC1), TRPC4, TRPC6, and calmodulin in PASMCs. In vivo studies demonstrated that ECH lowered the expression of these proteins in lung tissues of HPH rats, significantly decreased mean pulmonary artery pressure, and mitigated PVR.

The effects of physical exercise on ocular blood flow

Vascular resistance is physiologically regulated by changing the local diameter of the arterioles to keep the local blood flow constant. It is well known that physical activity has profound impacts on the vasculature in humans. Short‐term exercise induces immediate changes in artery function, whereas long‐term exercise induces chronic functional adaptation and structural arterial remodelling which leads to a lower risk of risk for cardiovascular disease. These changes depended on the characteristics of the training load and are modulated by other factors such as exercise‐induced inflammation and oxidative stress.The ocular circulation consists of the retinal and choroidal circulations. The retina is the tissue with the most active metabolism in the human body, resulting in a high rate of oxygen consumption. Therefore, ocular blood flow is particularly susceptible to physical exercise. With the arrival of imaging technologies numerous studies have explored the effects of exercise on the ocular blood flow. Most of these studies are focused on the transient impact of acute exercise on ocular blood flow. The objective of this talk is to discuss the scientific literature available about the effects of physical exercise on ocular blood flow, and to highlight its impact on ocular health.

FEATURES OF POLYURETHANE MATRIX REMODELING IN SHEEP MODEL EXPERIMENTS

HighlightsThe article describes the features of remodeling of polyurethane matrices during long-term implantation into the vascular bed of sheep. The results indicate high biocompatibility of polyurethane and resistance to bioresorption. The obtained data are significant for the development of medical products for cardiovascular surgery, in particular, biodegradable vascular prostheses. AbstractAim. To evaluate the features of polyurethane remodeling in a long-term experiment on a large animal model.Methods. Matrices made of 12% polyurethane solution in chloroform were manufactured by electrospinning at the Nanon-01A nanofiber electrospinning system (MIC, Japan). Matrix samples in the form of patches were implanted into the carotid arteries of sheep (n = 3) for a period of 6 months. The patency of vessels with implanted matrices was assessed after 2, 4 and 6 months using a portable hand-carried color Doppler - M7 Premium Ultrasound Machine (Mindray, China). The structure of the matrix surface before and after implantation was studied using an S-3400N scanning electron microscope (Hitachi, Japan). Histological examination of the explanted samples was carried out using an AXIO Imager A1 microscope (Carl Zeiss, Oberkochen, Germany) with previous staining of matrix sections with hematoxylin-eosin, Van Gieson and alizarin red C. Data processing was performed using the Statistica 6.0 software.Results. After 2, 4 and 6 months of implantation of polyurethane matrices into the carotid artery of sheep, complete patency of the carotid arteries was revealed. Macroscopically, after 6 months of implantation, the matrix completely resembled the carotid artery wall due to the full consolidation of the matrix with the artery wall and remodeling. Layers of newly formed vascular tissue – neointima and neoadventitia – were formed on the basis of the matrix. Histological examination revealed the structural integrity of the matrix without signs of inflammation and calcification both in the matrix structure and adjacent tissues.Conclusion. The biological inertia of polyurethane matrices with signs of remodeling was noted, which indicates a high biocompatibility of the material. Resistance to bioresorption and the ability to keep the frame of the product for a long time allows us to consider polyurethane as a suitable material for the formation of anti-aneurysmal protection of biodegradable vascular prostheses.

The structural rearrangement of testicular arteries in case of chronic ethanol intoxication

Prolonged poisoning of the body with ethanol damages almost all its organs and systems. Structural changes in testicular arteries under the influence of chronic ethanol intoxication have not been fully studied. Purpose - to analyze the morphometric parameters of the small caliber arteries of the right and left testicles of rats in case of chronic ethanol intoxication. Materials and methods. 62 laboratory sexually mature male rats was performed. The animals were divided into two groups. The Group 1 (control) included 30 rats, the Group 2 (experimental) - 32 animals. The experimental rats, which were conducted to the experiment, were injected intragastrically with a 30% ethanol solution at the rate of 2 ml per 100 g of body weight for 28 days once a day. Animals were euthanized by heart bleeding under thiopental anesthesia. Histological micro-sections were made from the left and right testicles. Morphometrically, the outer and inner diameters of the arteries, media thickness, adventitia, Vogenvoort and Kernogan indices, the height of endotheliocytes, the diameter of their nuclei, the nuclear-cytoplasmic ratio in these cells, and the relative volume of damaged endotheliocytes were determined morphometrically in small-caliber arteries. Statistical processing of digital data was carried out using Excel (Microsoft, USA) and STATISTICA 6.0 (Statsoft, USA) software. Results. It was established that in case of simulated experimental conditions of chronic ethanol intoxication, the investigated morphometric parameters of the arteries of the left and right testicles changed significantly. In case of chronic intoxication with ethanol in rats, pronounced structural rearrangement of testicular vessels, mainly small arteries, characterized by thickening of the blood vessel’s wall, narrowing of vessels’ lumen, rearrangement of endothelial cells, and an increase in the relative volume of the damaged cells of intima, is established, and is dominant in the left testis. Conclusions. In case of chronic intoxication with ethanol the structural changes in testicular tissues are dominant in the left testis. Pronounced remodeling of small caliber testicular arteries causes endothelial dysfunction, deterioration of blood supply to the testicles, hypoxia, dystrophic and necrobiotic tissue changes, infiltrative and sclerotic processes, which are the pathomorphological basis of male infertility. When carrying out experiments with laboratory animals, all bioethical norms and recommendations were observed. No conflict of interests was declared by the authors.

Single-cell RNA sequencing reveals association of aberrant placental trophoblasts and FN1 reduction in late-onset fetal growth restriction

IntroductionFetal growth restriction (FGR) can lead to fetal mental development abnormalities, malformations, and even intrauterine death. Defects in the trophoblasts at the maternal-fetal interface may contribute to FGR. However, the impact of trophoblasts on FGR is still not well understood. Therefore, the objective of this study is to characterize the heterogeneity of placental cells at the single-cell level and investigate the role of trophoblast subtypes in the pathogenesis of FGR at the cellular and molecular levels. MethodsSingle-cell RNA sequencing was performed on the maternal side of placentas from two normal pregnant women and two pregnant women with FGR. Lentivirus transfection was used to establish a FN1 knockout model in trophoblast HTR-8-Svneo cells. The effect of FN1 knockout on cell migration and invasion of HTR-8-Svneo cells was assessed through wound healing and transwell assays. ResultsNine cell types were annotated in 39,161 cells derived from single-cell RNA sequencing. The FGR group exhibited a decrease in the percentage of trophoblasts, especially in subtype of extravillous trophoblasts (EVTs). The expression of FN1 was reduced in trophoblasts and EVTs. Furthermore, the protein expression levels of FN1 in the placentas of FGR patients were significantly lower than those of normal pregnant women. The cell migration and invasion ability of HTR-8-Svneo cells were inhibited after the knockdown of FN1. DiscussionThe dysregulation of the trophoblast subtype-EVTs is involved in placental dysplasia related to FGR. The association between aberrant placental trophoblasts and reduced FN1 expression may contribute to insufficient remodeling of spiral arteries and the formation of FGR.

Normotensive placental extracellular vesicles provide long-term protection against hypertension and cardiovascular disease

BackgroundWomen with normotensive pregnancy are at a reduced risk of developing cardiovascular disease postpartum compared to those who experience hypertensive conditions during pregnancy. However, the underlying mechanisms remain poorly understood. During normotensive pregnancy, vast numbers of placental extracellular vesicles are released into the maternal circulation, which protect endothelial cells from activation and alter maternal vascular tone. We hypothesized that placental extracellular vesicles play a mechanistic role in lowering risk of cardiovascular disease following normotensive pregnancy. ObjectiveThis study aimed to investigate the long-term effects of placental extracellular vesicles derived from normotensive term placentae on the cardiovascular system and explore the mechanisms underlying their biological effects. Study DesignSpontaneously hypertensive rats were injected with placental EVs from normotensive term pregnancies (2 mg /kg each time, n=8) or vehicle control (n=9) at 3 months of age. Blood pressure and cardiac function were regularly monitored from 3 months to 15 months of age. The response of mesenteric resistance arteries to vasoactive substances was investigated to evaluate vascular function. Cardiac remodelling, small artery remodelling, and renal function were investigated to comprehensively assess the impact of placental extracellular vesicles on cardiovascular and renal health. ResultsCompared to vehicle-treated control animals, rats treated with normotensive placental extracellular vesicles exhibited a significantly lower increase in blood pressure and improved cardiac function. Furthermore, the vasodilator response to the endothelium-dependent agonist acetylcholine was significantly enhanced in the normotensive placental extracellular vesicle-treated spontaneously hypertensive rats compared to the control. Moreover, treatment with placental extracellular vesicles reduced wall thickening of small renal vessels and attenuated renal fibrosis. ConclusionPlacental extracellular vesicles from normotensive term pregnancies have long-lasting protective effects reducing hypertension and mitigating cardiovascular damage in vivo.

Inhibition of DYRK1A attenuates vascular remodeling in pulmonary arterial hypertension via suppressing STAT3/Pim-1/NFAT pathway

ABSTRACT Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling caused by the excessive proliferation and survival of pulmonary artery smooth muscle cells (PASMCs). Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in the regulation of multiple biological functions, including cell proliferation and survival. However, the role and underlying mechanisms of DYRK1A in PAH pathogenesis remain unclear. We found that DYRK1A was upregulated in PASMCs in response to hypoxia, both in vivo and in vitro. Inhibition of DYRK1A by harmine significantly attenuated hypoxia-induced pulmonary hypertension and pulmonary artery remodeling. Mechanistically, we found that DYRK1A promoted pulmonary arterial remodeling by enhancing the proliferation and survival of PASMCs through activating the STAT3/Pim-1/NFAT pathway, because STAT3 gain-of-function via adeno-associated virus serotype 2 (AAV2) carrying the constitutively active form of STAT3 (STAT3C) nearly abolished the protective effect of harmine on PAH. Collectively, our results reveal a significant role for DYRK1A in pulmonary arterial remodeling and suggest it as a drug target with translational potential for the treatment of PAH.

The FXYD1 protein plays a protective role against pulmonary hypertension and arterial remodeling via redox and inflammatory mechanisms.

Pulmonary hypertension (PH) consists of a heterogenous group of diseases that culminate in increased pulmonary arterial pressure and right ventricular (RV) dysfunction. We sought to investigate the role of FXYD1, a small membrane protein that modulates Na+-K+-ATPase function, in the pathophysiology of PH. We mined online transcriptome databases to assess FXYD1 expression in PH. We characterized the effects of FXYD1 knockout (KO) in mice on right and left ventricular (RV and LV) function using echocardiography and measured invasive hemodynamic measurements under normal conditions and after treatment with bleomycin sulfate or chronic hypoxia to induce PH. Using immunohistochemistry, immunoblotting, and functional assays, we examined the effects of FXYD1 KO on pulmonary microvasculature and RV and LV structure and assessed signaling via endothelial nitric oxide synthase (eNOS) and inflammatory pathways. FXYD1 lung expression tended to be lower in samples from patients with idiopathic pulmonary arterial hypertension (IPAH) compared with controls, supporting a potential pathophysiological role. FXYD1 KO mice displayed characteristics of PH including significant increases in pulmonary arterial pressure, increased muscularization of small pulmonary arterioles, and impaired RV systolic function, in addition to LV systolic dysfunction. However, when PH was stimulated with standard models of lung injury-induced PH, there was no exacerbation of disease in FXYD1 KO mice. Both the lungs and left ventricles exhibited elevated nitrosative stress and inflammatory milieu. The absence of FXYD1 in mice results in LV inflammation and cardiopulmonary redox signaling changes that predispose to pathophysiological features of PH, suggesting FXYD1 may be protective.NEW & NOTEWORTHY This is the first study to show that deficiency of the FXYD1 protein is associated with pulmonary hypertension. FXYD1 expression is lower in the lungs of people with idiopathic pulmonary artery hypertension. FXYD1 deficiency results in both left and right ventricular functional impairment. Finally, FXYD1 may endogenously protect the heart from oxidative and inflammatory injury.

COMPARISON OF OXIDATIVE STRESS LEVELS DURING THE THIRD TRIMESTER IN NORMAL PREGNANCY AND PREECLAMPSIA

Background: The placenta is a complex transiently formed organ which plays a crucial role in the development of the foetus. As the placenta is responsible for maintaining pregnancy placental defects are mainly responsible for pregnancy-related issues. Preeclampsia is a pregnancy-related disorder due to uteroplacental insufficiency resulting from deficient remodelling of spiral arteries causing ischemic reperfusion injury which is finally responsible for the generation of reactive oxygen species and oxidative stress by the placenta. So, this study was planned to determine and compare serum levels of oxidative stress markers (ischemia-modified albumin and malondialdehyde) in preeclampsia and normal pregnancy in the third trimester. Methods: Study design: Cross-sectional comparative study Settings Gynae/Obs Department and Pathology Laboratory, Lahore General Hospital, Lahore. Study population: 42 Pregnant females at 34–36 weeks of gestation were selected. Group 1 compromised 21 normal healthy pregnant females and group 2 included 21 preeclamptic patients. Sampling technique: non-probability purposive sampling. Blood samples were taken at 34–36 weeks of gestation. Serum was stored for ischemia-modified albumin and malondialdehyde. Data was analyzed using SPSS version 20. An Independent t-test was used to compare values between the groups during the third trimester. A p-value of ≤0.05 was considered significant. Results: Comparison of ischemia-modified albumin and malondialdehyde values between group I and group 2 showed a highly significant difference of p-value of <0.001. Conclusion: Oxidative stress markers were higher in preeclamptic patients as compared to normal pregnant females during the third trimester suggesting the role of the placenta in oxidative stress.

Endothelial to mesenchymal transition is an active process in smokers and patients with early COPD contributing to pulmonary arterial pathology.

We have previously reported pulmonary arterial remodelling in smokers and patients with early COPD, which can be attributed to endothelial to mesenchymal transition (EndMT). In this study, we aimed to evaluate if EndMT is an active mechanism in smokers and COPD. Immunohistochemical staining for the EndMT biomarkers CD31, N-cadherin, vimentin and S100A4 was done on lung resection tissue from 49 subjects. These comprised 15 nonsmoker controls (NC), six normal lung function smokers (NLFS), nine patients with small airway disease (SAD), nine current smokers with mild-moderate COPD (COPD-CS) and 10 ex-smokers with COPD (COPD-ES). Pulmonary arteries were analysed using Image ProPlus software v7.0. We noted reduced junctional CD31+ endothelial cells (p<0.05) in the intimal layer of all smoking groups compared to NC. We also observed increased abundance of the mesenchymal markers N-cadherin (p<0.05) and vimentin (p<0.001) in all smoking groups and across all arterial sizes versus NC, except for N-cadherin in large arteries in COPD-CS. The abundance of S100A4 correlated with arterial thickness (small: r=0.29, p=0.05; medium: r=0.33, p=0.03; large: r=0.35, p=0.02). Vimentin in the small arterial wall negatively correlated with forced expiratory volume in 1 s/forced vital capacity (r= -0.35, p=0.02) and forced expiratory flow rate at 25-75% of forced vital capacity (r= -0.34, p=0.03), while increased cytoplasmic CD31 abundance in the intimal layer of medium and large arteries negatively correlated with predicted diffusing capacity of the lung for carbon monoxide (medium: r= -0.35, p=0.04; large: r= -0.39, p=0.03). This is the first study showing the acquisition of mesenchymal traits by pulmonary endothelial cells from NLFS, SAD and mild-moderate COPD patients through EndMT. This informs on the potential early origins of pulmonary hypertension in smokers and patients with early COPD.