Exercise mitigates flow recirculation and activates metabolic transducer SCD1 to catalyze vascular protective metabolites.

Exercise promotes pulsatile shear stress in the arterial circulation and ameliorates cardiometabolic diseases. However, exercise-mediated metabolic transducers for vascular protection remain under-investigated. Untargeted metabolomic analysis demonstrated that wild-type mice undergoing voluntary wheel running exercise expressed increased endothelial stearoyl-CoA desaturase 1 (SCD1) that catalyzes anti-inflammatory lipid metabolites, namely, oleic (OA) and palmitoleic acids (PA), to mitigate NF-κB-mediated inflammatory responses.

Exercise Mitigates Flow Recirculation and Activates Mechanosensitive Transcriptome to Uncover Endothelial SCD1-Catalyzed Anti-Inflammatory Metabolites.

Exercise modulates vascular plasticity in multiple organ systems; however, the metabolomic transducers underlying exercise and vascular protection in the disturbed flow-prone vasculature remain under-investigated. We simulated exercise-augmented pulsatile shear stress (PSS) to mitigate flow recirculation in the lesser curvature of the aortic arch. When human aortic endothelial cells (HAECs) were subjected to PSS ( = 50 dyne·cm , ∂τ/∂t = 71 dyne·cm ·s , 1 Hz), untargeted metabolomic analysis revealed that Stearoyl-CoA Desaturase (SCD1) in the endoplasmic reticulum (ER) catalyzed the fatty acid metabolite, oleic acid (OA), to mitigate inflammatory mediators.

Endothelial mechanotransduction in cardiovascular development and regeneration: emerging approaches and animal models.

Living cells are exposed to multiple mechanical stimuli from the extracellular matrix or from surrounding cells. Mechanoreceptors are molecules that display status changes in response to mechanical stimulation, transforming physical cues into biological responses to help the cells adapt to dynamic changes of the microenvironment. Mechanical stimuli are responsible for shaping the tridimensional development and patterning of the organs in early embryonic stages.

Rapid Detection and Inhibition of SARS-CoV-2-Spike Mutation-Mediated Microthrombosis.

Activation of endothelial cells following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be the primary driver for the increasingly recognized thrombotic complications in coronavirus disease 2019 patients, potentially due to the SARS-CoV-2 Spike protein binding to the human angiotensin-converting enzyme 2 (hACE2). Vaccination therapies use the same Spike sequence or protein to boost host immune response as a protective mechanism against SARS-CoV-2 infection. As a result, cases of thrombotic events are reported following vaccination.

Noggin depletion in adipocytes promotes obesity in mice.

Objective: Obesity has increased to pandemic levels and enhanced understanding of adipose regulation is required for new treatment strategies. Although bone morphogenetic proteins (BMPs) influence adipogenesis, the effect of BMP antagonists such as Noggin is largely unknown. The aim of the study was to define the role of Noggin, an extracellular BMP inhibitor, in adipogenesis.

Beyond the bone: Bone morphogenetic protein signaling in adipose tissue.

The bone morphogenetic proteins (BMPs) belong to the same superfamily as related to transforming growth factor β (TGFβ), growth and differentiation factors (GDFs), and activins. They were initially described as inducers of bone formation but are now known to be involved in morphogenetic activities and cell differentiation throughout the body, including the development of adipose tissue and adipogenic differentiation. BMP4 and BMP7 are the most studied BMPs in adipose tissue, with major roles in white adipogenesis and brown adipogenesis, respectively, but other BMPs such as BMP2, BMP6, and BMP8b as well as some inhibitors and modulators have been shown to also affect adipogenesis.

Generation of Vascular Networks from Adipocytes .

Multipotent cells derived from white mature adipocytes, referred to as dedifferentiated fat (DFAT) cells have the capacity differentiate into endothelial cells. The objective of this study was to modify the isolation method for DFAT cells in order to optimize the endothelial lineage potential. The adipocytes were preincubated for 24 hours, washed, and then incubated for 5 days to allow the generated DFAT cells to remain in proximity to the adipocytes while the cells aggregated into cell clusters.

Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation.

The vascular endothelium is critical for induction of appropriate lineage differentiation in organogenesis. In this study, we report that dysfunctional pulmonary endothelium, resulting from the loss of matrix Gla protein (MGP), causes ectopic hepatic differentiation in the pulmonary epithelium. We demonstrate uncontrolled induction of the hepatic growth factor (HGF) caused by dysregulated cross talk between pulmonary endothelium and epithelium in -null lungs.

Endothelial-Mesenchymal Transition in Vascular Calcification of Ins2Akita/+ Mice.

Endothelial-mesenchymal transition (EndMT) drives endothelium to contribute to normal development and disease processes. Here, we report that EndMTs occur in the diabetic endothelium of Ins2Akita/wt mouse, and show that induction of sex determining region Y-box 2 (Sox2) is a mediator of excess BMP signaling that results in activation of EndMTs and increased vascular calcification. We also find an induction of a complex of serine proteases in the diabetic endothelium, required for the up-regulation of Sox2.

Endothelial-mesenchymal transition in atherosclerotic lesion calcification.

Background And Aims: Endothelial-mesenchymal transitions (EndMTs) in endothelial cells (ECs) contribute to vascular disease.

Methods: We used ApoE mice fed a high-fat/high-cholesterol diet.

Results: We reported evidence of EndMT in atherosclerotic lesions contributing to calcification.

Serum Superoxide Dismutase Is Associated with Vascular Structure and Function in Hypertensive and Diabetic Patients.

Oxidative stress is associated with cardiac and vascular defects leading to hypertension and atherosclerosis, being superoxide dismutase (SOD) one of the main intracellular antioxidant defence mechanisms. Although several parameters of vascular function and structure have a predictive value for cardiovascular morbidity-mortality in hypertensive patients, there are no studies on the involvement of SOD serum levels with these vascular parameters. Thus, we assessed if SOD serum levels are correlated with parameters of vascular function and structure and with cardiovascular risk in hypertensive and type 2 diabetic patients.

Increased Klk9 Urinary Excretion Is Associated to Hypertension-Induced Cardiovascular Damage and Renal Alterations.

Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys.We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage.

Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells.

Matrix Gla protein (MGP) is an antagonist of bone morphogenetic proteins and expressed in vascular endothelial cells. Lack of MGP causes vascular abnormalities in multiple organs in mice. The objective of this study is to define the role of MGP in early endothelial differentiation.

Serine Protease Activation Essential for Endothelial-Mesenchymal Transition in Vascular Calcification.

Rationale: Endothelial cells have the ability to undergo endothelial-mesenchymal transitions (EndMTs), by which they acquire a mesenchymal phenotype and stem cell-like characteristics. We previously found that EndMTs occurred in the endothelium deficient in matrix γ-carboxyglutamic acid protein enabling endothelial cells to contribute cells to vascular calcification. However, the mechanism responsible for initiating EndMTs is not fully understood.

ABCC6 deficiency is associated with activation of BMP signaling in liver and kidney.

Mutations in ABCC6 (ATP-binding cassette, subfamily C, member 6), an orphan transporter expressed in the liver, are the cause of pseudoxanthoma elasticum. Since ABCC6 was reported to affect matrix Gla protein (MGP), an inhibitor of bone morphogenetic proteins (BMPs), we studied BMP signaling and expression in various tissues of mice with and without functional ABCC. Enhanced BMP signaling was found in all examined tissues in the absence of ABCC6.

Hypertension and hyperglycemia synergize to cause incipient renal tubular alterations resulting in increased NGAL urinary excretion in rats.

Background: Hypertension and diabetes are the two leading causes of chronic kidney disease (CKD) eventually leading to end stage renal disease (ESRD) and the need of renal replacement therapy. Mortality among CKD and ESRD patients is high, mostly due to cardiovascular events. New early markers of risk are necessary to better anticipate the course of the disease, to detect the renal affection of additive risk factors, and to appropriately handle patients in a pre-emptive and personalized manner.

Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency.

Cerebral arteriovenous malformations (AVMs) are common vascular malformations, which may result in hemorrhagic strokes and neurological deficits. Bone morphogenetic protein (BMP) and Notch signaling are both involved in the development of cerebral AVMs, but the cross-talk between the two signaling pathways is poorly understood. Here, we show that deficiency of matrix Gla protein (MGP), a BMP inhibitor, causes induction of Notch ligands, dysregulation of endothelial differentiation, and the development of cerebral AVMs in MGP null (Mgp(-/-)) mice.

Concerted action of ANP and dopamine D1-receptor to regulate sodium homeostasis in nephrotic syndrome.

The edema formation in nephrotic syndrome (NS) is associated with a blunted response to atrial natriuretic peptide (ANP). The natriuretic effects of ANP have been related to renal dopamine D1-receptors (D1R). We examined the interaction between ANP and renal D1R in rats with puromycin aminonucleoside-induced NS (PAN-NS).

H-Ras isoform modulates extracellular matrix synthesis, proliferation, and migration in fibroblasts.

Ras GTPases are ubiquitous plasma membrane transducers of extracellular stimuli. In addition to their role as oncogenes, Ras GTPases are key regulators of cell function. Each of the Ras isoforms exhibits specific modulatory activity on different cellular pathways.

Osteoprotegerin is associated with cardiovascular risk in hypertension and/or diabetes.

Background: Osteoprotegerin (OPG), a secreted member of the tumour necrosis factor receptor superfamily of cytokines, has been associated with endothelial dysfunction. We studied in type 2 diabetic and/or hypertensive patients the relationship between serum OPG and vascular alterations associated with these pathologies.

Materials And Methods: We analysed 191 consecutive patients (52 with type 2 diabetes and 139 hypertensive nondiabetic patients) and 54 healthy controls.

Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and diabetic patients.

Background: Endoglin is involved in the regulation of endothelial function, but there are no studies concerning its relation with hypertension- and diabetes-associated pathologies. Thus, we studied the relationship between plasma levels of soluble endoglin and cardiovascular alterations associated with hypertension and diabetes.

Methods: We analyzed 288 patients: 64 with type 2 diabetes, 159 with hypertension and 65 healthy patients.

Analysis of k-ras nuclear expression in fibroblasts and mesangial cells.

Background: Ras GTPases are considered cytoplasmic proteins that must be localized to cell membranes for activation, and there are few evidences of the presence of any Ras isoform in nuclei of eukaryotic cells.

Methodology/principal Findings: Using conventional antibodies and inmunocytochemistry, differential centrifugation and western blot, we have observed the putative presence of K-Ras isoform in the nuclei of fibroblasts and mesangial cells. In order to avoid cross-reactions with other Ras isoforms, and using antibodies against K-Ras (R-3400, H3845-M01, sc-30) or pan-Ras (05-516, OP40) in cells that only expressed the K-Ras isoform (fibroblasts obtained from H-ras(-/-),N-ras(-/-) mice) we also detected some nuclear positive expression.

Mechanisms involved in the genesis of diabetic nephropathy.

In recent years, the amount of people suffering from diabetes has increased notably. This increase has led to an augmentation in secondary diseases; amongst them, diabetic nephropathy (DN) is one of the most relevant pathologies. DN provokes a decrease in glomerular filtration rate, which ends up in chronic renal failure.