Special features on insulin resistance, metabolic syndrome and vascular complications in hypopituitary patients.

Pituitary hormone deficiency, hypopituitarism, is a dysfunction resulting from numerous etiologies, which can be complete or partial, and is therefore heterogeneous. This heterogeneity makes it difficult to interpret the results of scientific studies with these patients.Adequate treatment of etiologies and up-to-date hormone replacement have improved morbidity and mortality rates in patients with hypopituitarism. As GH replacement is not performed in a reasonable proportion of patients, especially in some countries, it is essential to understand the known consequences of GH replacement in each subgroup of patients with this heterogeneous dysfunction.In this review on hypopituitarism, we will address some particularities regarding insulin resistance, which is no longer common in these patients with hormone replacement therapy based on current guidelines, metabolic syndrome and its relationship with changes in BMI and body composition, and to vascular complications that need to be prevented taking into account the individual characteristics of each case to reduce mortality rates in these patients.

Isolation and primary culture of human abdominal aorta smooth muscle cells from brain-dead donors: an experimental model for vascular diseases.

Primary cell cultures are essential tools for elucidating the physiopathological mechanisms of the cardiovascular system. Therefore, a primary culture growth protocol of cardiovascular smooth muscle cells (VSMCs) obtained from human abdominal aortas was standardized. Ten abdominal aorta samples were obtained from patients diagnosed with brain death who were organ and tissue donors with family consent. After surgical ablation to capture the aorta, the aortic tissue was removed, immersed in a Custodiol® solution, and kept between 2 and 8 °C. In the laboratory, in a sterile environment, the tissue was fragmented and incubated in culture plates containing an enriched culture medium (DMEM/G/10% fetal bovine serum, L-glutamine, antibiotics and antifungals) and kept in an oven at 37 °C and 5% CO2. The aorta was removed after 24 h of incubation, and the culture medium was changed every six days for twenty days. Cell growth was confirmed through morphological analysis using an inverted optical microscope (Nikon®) and immunofluorescence for smooth muscle alpha-actin and nuclei. The development of the VSMCs was observed, and from the twelfth day, differentiation, long cytoplasmic projections, and adjacent cell connections occurred. On the twentieth day, the morphology of the VSMCs was confirmed by actin fiber immunofluorescence, which is a typical characteristic of VSMCs. The standardization allowed VSMC growth and the replicability of the in vitro test, providing a protocol that mimics natural physiological environments for a better understanding of the cardiovascular system. Its use is intended for investigation, tissue bioengineering, and pharmacological treatments.

Blood-brain barrier lesion - a novel determinant of autonomic imbalance in heart failure and the effects of exercise training.

Heart failure (HF) is characterized by reduced ventricular function, compensatory activation of neurohormonal mechanisms and marked autonomic imbalance. Exercise training (T) is effective to reduce neurohormonal activation but the mechanism underlying the autonomic dysfunction remains elusive. Knowing that blood-brain barrier (BBB) lesion contributes to autonomic imbalance, we sought now to investigate its involvement in HF- and exercise-induced changes of autonomic control. Wistar rats submitted to coronary artery ligation or SHAM surgery were assigned to T or sedentary (S) protocol for 8 weeks. After hemodynamic/autonomic recordings and evaluation of BBB permeability, brains were harvesting for ultrastructural analysis of BBB constituents, measurement of vesicles trafficking and tight junction's (TJ) tightness across the BBB (transmission electron microscopy) and caveolin-1 and claudin-5 immunofluorescence within autonomic brain areas. HF-S rats versus SHAM-S exhibited reduced blood pressure, augmented vasomotor sympathetic activity, increased pressure and reduced heart rate variability, and, depressed reflex sensitivity. HF-S also presented increased caveolin-1 expression, augmented vesicle trafficking and a weak TJ (reduced TJ extension/capillary border), which determined increased BBB permeability. In contrast, exercise restored BBB permeability, reduced caveolin-1 content, normalized vesicles counting/capillary, augmented claudin-5 expression, increased TJ tightness and selectivity simultaneously with the normalization of both blood pressure and autonomic balance. Data indicate that BBB dysfunction within autonomic nuclei (increased transcytosis and weak TJ allowing entrance of plasma constituents into the brain parenchyma) underlies the autonomic imbalance in HF. Data also disclose that exercise training corrects both transcytosis and paracellular transport and improves autonomic control even in the persistence of cardiac dysfunction.

Impact of Acute High Glucose on Mitochondrial Function in a Model of Endothelial Cells: Role of PDGF-C.

An increase in plasma high glucose promotes endothelial dysfunction mainly through increasing mitochondrial ROS production. High glucose ROS-induced has been implicated in the fragmentation of the mitochondrial network, mainly by an unbalance expression of mitochondrial fusion and fission proteins. Mitochondrial dynamics alterations affect cellular bioenergetics. Here, we assessed the effect of PDGF-C on mitochondrial dynamics and glycolytic and mitochondrial metabolism in a model of endothelial dysfunction induced by high glucose. High glucose induced a fragmented mitochondrial phenotype associated with the reduced expression of OPA1 protein, high DRP1pSer616 levels and reduced basal respiration, maximal respiration, spare respiratory capacity, non-mitochondrial oxygen consumption and ATP production, regarding normal glucose. In these conditions, PDGF-C significantly increased the expression of OPA1 fusion protein, diminished DRP1pSer616 levels and restored the mitochondrial network. On mitochondrial function, PDGF-C increased the non-mitochondrial oxygen consumption diminished by high glucose conditions. These results suggest that PDGF-C modulates the damage induced by HG on the mitochondrial network and morphology of human aortic endothelial cells; additionally, it compensates for the alteration in the energetic phenotype induced by HG.

Platelets and endothelial dysfunction in gestational diabetes mellitus.

The prevalence of gestational diabetes mellitus (GDM) has increased in recent years, along with the higher prevalence of obesity in women of reproductive age. GDM is a pathology associated with vascular dysfunction in the fetoplacental unit. GDM-associated endothelial dysfunction alters the transfer of nutrients to the foetus affecting newborns and pregnant women. Various mechanisms for this vascular dysfunction have been proposed, of which the most studied are metabolic alterations of the vascular endothelium. However, different cell types are involved in GDM-associated endothelial dysfunction, including platelets. Platelets are small, enucleated cell fragments that actively take part in blood haemostasis and thrombus formation. Thus, they play crucial roles in pathologies coursing with endothelial dysfunction, such as atherosclerosis, cardiovascular diseases, and diabetes mellitus. Nevertheless, platelet function in GDM is understudied. Several reports show a potential relationship between platelet volume and mass with GDM; however, platelet roles and signaling mechanisms in GDM-associated endothelial dysfunction are unclear. This review summarizes the reported findings and proposes a link among altered amount, volume, mass, reactivity, and function of platelets and placenta development, resulting in fetoplacental vascular dysfunction in GDM.

Local delivery of nitric oxide prevents endothelial dysfunction in periodontitis.

AIMS: Increased cardiovascular disease risk underlies elevated rates of mortality in individuals with periodontitis. A key characteristic of those with increased cardiovascular risk is endothelial dysfunction, a phenomenon synonymous with deficiencies of bioavailable nitric oxide (NO), and prominently expressed in patients with periodontitis. Also, inorganic nitrate can be reduced to NO in vivo to restore NO levels, leading us to hypothesise that its use may be beneficial in reducing periodontitis-associated endothelial dysfunction. Herein we sought to determine whether inorganic nitrate improves endothelial function in the setting of periodontitis and if so to determine the mechanisms underpinning any responses seen. METHODS AND RESULTS: Periodontitis was induced in mice by placement of a ligature for 14 days around the second molar. Treatment in vivo with potassium nitrate, either prior to or following establishment of experimental periodontitis, attenuated endothelial dysfunction, as determined by assessment of acetylcholine-induced relaxation of aortic rings, compared to control (potassium chloride treatment). These beneficial effects were associated with a suppression of vascular wall inflammatory pathways (assessed by quantitative-PCR), increases in the anti-inflammatory cytokine interleukin (IL)-10 and reduced tissue oxidative stress due to attenuation of xanthine oxidoreductase-dependent superoxide generation. In patients with periodontitis, plasma nitrite levels were not associated with endothelial function indicating dysfunction. CONCLUSION: Our results suggest that inorganic nitrate protects against, and can partially reverse pre-existing, periodontitis-induced endothelial dysfunction through restoration of nitrite and thus NO levels. This research highlights the potential of dietary nitrate as adjunct therapy to target the associated negative cardiovascular outcomes in patients with periodontitis.

TGF-ß1 Reduces Neutrophil Adhesion and Prevents Acute Vaso-Occlusive Processes in Sickle Cell Disease Mice.

Sickle cell disease (SCD) patients experience chronic inflammation and recurrent vaso-occlusive episodes during their entire lifetime. Inflammation in SCD occurs with the overexpression of several inflammatory mediators, including transforming growth factor beta-1 (TGF-ß1), a major immune regulator. In this study, we aimed to investigate the role played by TGF-ß1 in vascular inflammation and vaso-occlusion in an animal model of SCD. Using intravital microscopy, we found that a daily dose of recombinant TGF-ß1 administration for three consecutive days significantly reduced TNFα-induced leukocyte rolling, adhesion, and extravasation in the microcirculation of SCD mice. In contrast, immunological neutralization of TGF-ß, in the absence of inflammatory stimulus, considerably increased these parameters. Our results indicate, for the first time, that TGF-ß1 may play a significant ameliorative role in vascular SCD pathophysiology, modulating inflammation and vaso-occlusion. The mechanisms by which TGF-ß1 exerts its anti-inflammatory effects in SCD, however, remains unclear. Our in vitro adhesion assays with TNFα-stimulated human neutrophils suggest that TGF-ß1 can reduce the adhesive properties of these cells; however, direct effects of TGF-ß1 on the endothelium cannot be ruled out. Further investigation of the wide range of the complex biology of this cytokine in SCD pathophysiology and its potential therapeutical use is needed.

Topiramate treatment in Wistar rats during childhood induces sex-specific vascular dysfunction in adulthood.

The present study determined whether treatment during childhood with topiramate (TPM), a new generation antiepileptic drug, results in altered aortic reactivity in adult male and female rats. We also sought to understand the role of endothelium-derived contractile factors in TPM-induced vascular dysfunction. Male and female Wistar rats were treated with TPM (41 mg/kg/day) or water (TPM vehicle) by gavage during childhood (postnatal day, 16-28). In adulthood, thoracic aorta reactivity to phenylephrine (phenyl), as well as aortic thickness and expression of cyclooxygenases (COX-1 and COX-2), NOX2, and p47phox were evaluated. The aortic response to phenyl was increased in male and female rats from the TPM group when compared with the control group. In TPM male rats, the hyperreactivity to phenyl was abrogated by the inhibition of NADPH oxidase and COX-2, while in female rats, responses were restored only by inhibition of COX-2. In addition, TPM male rats presented aortic hypertrophy and increased expression of NOX-2 and p47phox, while TPM female rats showed increased COX-2 aortic expression. Taken together, for the first-time, the present study provides evidence that treatment with TPM during childhood causes vascular dysfunction in adulthood, and that the mechanism underlying the vascular effects of TPM is sex-specific.

Characterization of a murine model of endothelial dysfunction induced by chronic intraperitoneal administration of angiotensin II.

Endothelial dysfunction (ED) is a key factor for the development of cardiovascular diseases. Due to its chronic, life-threatening nature, ED only can be studied experimentally in animal models. Therefore, this work was aimed to characterize a murine model of ED induced by a daily intraperitoneal administration of angiotensin II (AGII) for 10 weeks. Oxidative stress, inflammation, vascular remodeling, hypertension, and damage to various target organs were evaluated in treated animals. The results indicated that a chronic intraperitoneal administration of AGII increases the production of systemic soluble VCAM, ROS and ICAM-1 expression, and the production of TNFα, IL1ß, IL17A, IL4, TGFß, and IL10 in the kidney, as well as blood pressure levels; it also promotes vascular remodeling and induces non-alcoholic fatty liver disease, glomerulosclerosis, and proliferative retinopathy. Therefore, the model herein proposed can be a representative model for ED; additionally, it is easy to implement, safe, rapid, and inexpensive.

Aldosterone Negatively Regulates Nrf2 Activity: An Additional Mechanism Contributing to Oxidative Stress and Vascular Dysfunction by Aldosterone.

High levels of aldosterone (Aldo) trigger oxidative stress and vascular dysfunction independent of effects on blood pressure. We sought to determine whether Aldo disrupts Nrf2 signaling, the main transcriptional factor involved in antioxidant responses that aggravate cell injury. Thoracic aorta from male C57Bl/6J mice and cultured human endothelial cells (EA.hy926) were stimulated with Aldo (100 nM) in the presence of tiron [reactive oxygen species (ROS) scavenger, eplerenone [mineralocorticoid receptor (MR) antagonist], and L-sulforaphane (SFN; Nrf2 activator). Thoracic aortas were also isolated from mice infused with Aldo (600 µg/kg per day) for 14 days. Aldo decreased endothelium-dependent vasorelaxation and increased ROS generation, effects prevented by tiron and MR blockade. Pharmacological activation of Nrf2 with SFN abrogated Aldo-induced vascular dysfunction and ROS generation. In EA.hy926 cells, Aldo increased ROS generation, which was prevented by eplerenone, tiron, and SFN. At short times, Aldo-induced ROS generation was linked to increased Nrf2 activation. However, after three hours, Aldo decreased the nuclear accumulation of Nrf2. Increased Keap1 protein expression, but not activation of p38 MAPK, was linked to Aldo-induced reduced Nrf2 activity. Arteries from Aldo-infused mice also exhibited decreased nuclear Nrf2 and increased Keap1 expression. Our findings suggest that Aldo reduces vascular Nrf2 transcriptional activity by Keap1-dependent mechanisms, contributing to mineralocorticoid-induced vascular dysfunction.

Focal adhesion signaling: vascular smooth muscle cell contractility beyond calcium mechanisms.

Smooth muscle cell (SMC) contractility is essential to vessel tone maintenance and blood pressure regulation. In response to vasoconstrictors, calcium-dependent mechanisms promote the activation of the regulatory myosin light chain, leading to increased cytoskeleton tension that favors cell shortening. In contrast, SMC maintain an intrinsic level of a contractile force independent of vasoconstrictor stimulation and sustained SMC contraction beyond the timescale of calcium-dependent mechanisms suggesting the involvement of additional players in the contractile response. Focal adhesions (FAs) are conceivable candidates that may influence SMC contraction. They are required for actin-based traction employed by cells to sense and respond to environmental cues in a process termed mechanotransduction. Depletion of FA proteins impairs SMC contractility, producing arteries that are prone to dissection because of a lack of mechanical stability. Here, we discuss the role of calcium-independent FA signaling mechanisms in SMC contractility. We speculate that FA signaling contributes to the genesis of a variety of SMC phenotypes and discuss the potential implications for mechanical homeostasis in normal and diseased states.

Experimental Periodontal Disease Triggers Coronary Endothelial Dysfunction in Middle-Aged Rats: Preventive Effect of a Prebiotic ß-Glucan.

This study was aimed to verify the hypothesis that periodontal disease contributes to endothelial dysfunction in the coronary arteries of middle-aged rats. Besides we evaluated the effects of a prebiotic (ß-glucan isolated from Saccharomyces cerevisiae) in preventing vascular dysfunction. The sample comprised young (sham and induced to periodontal disease) and middle-aged rats (sham, periodontal disease, sham-treated and periodontal disease-treated), at 12 and 57 weeks, respectively. The treated-groups received daily doses of ß-glucan (50 mg/kg) orally (gavage) for 4 weeks, and periodontal disease was induced in the last 2 weeks by ligature. A myograph system assessed vascular reactivity. The expression of endothelial nitric oxide synthase (eNOS), cyclooxygenase 1 (COX-1), COX-2, p47phox, gp91phox, NF-KB p65, p53, p21, and p16 was quantified by western blotting. Serum hydroperoxide production was measured by the ferrous oxidation-xylenol orange (FOX-2) assay method. Interleukin-1 beta (IL-1ß), IL-10, and tumor necrosis factor-alpha (TNF-α) levels were evaluated by spectroscopic ultraviolet-visible analysis. Periodontal disease in middle-aged rats was associated with reduced acetylcholine-induced relaxations of coronary artery rings affecting the endothelium-dependent hyperpolarization- and the nitric oxide-mediated relaxations. The endothelial dysfunction was related to eNOS downregulation, pronounced impairment of the EDH-mediated relaxation, increased IL-1ß and TNF-α proinflammatory cytokines, and also upregulation of NADPH oxidase and COXs, starting accumulate aging markers such as p53/p21 and the p16. Treatment with ß-glucan effectively reduced bone loss in periodontal disease and delayed endothelial dysfunction in the coronary artery. Our data show that yeast ß-glucan ingestion prevented oxidative stress and synthesis of proinflammatory marker and prevented eNOS reduction induced by periodontal disease in middle-aged rats. These results suggest that ß-glucan has a beneficial effect on the coronary vascular bed.

Immunological Hallmarks of Inflammatory Status in Vaso-Occlusive Crisis of Sickle Cell Anemia Patients.

Sickle Cell Anemia (SCA) is the most common genetic disorder around the world. The mutation in the ß-globin gene is responsible for a higher hemolysis rate, with further involvement of immunological molecules, especially cytokines, chemokines, growth factors, and anaphylatoxins. These molecules are responsible for inducing and attracting immune cells into circulation, thus contributing to increases in leukocytes and other pro-inflammatory mediators, and can culminate in a vaso-occlusive crisis (VOC). This study aimed to characterize the levels of these molecules in SCA patients in different clinical conditions in order to identify potential hallmarks of inflammation in these patients. An analytical prospective study was conducted using the serum of SCA patients in steady-state (StSt; n = 27) and VOC (n = 22), along with 53 healthy donors (HD). Samples from the VOC group were obtained on admission and on discharge, in the convalescent phase (CV). Levels of chemokines (CXCL8, CXCL10, CL2, CLL3, CCL4, CL5, and CCL11), cytokines (IL-1ß, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12p70, IL-13, IL-17A, TNF-α, and IFN-γ) and growth factors (VEGF, FGFb, PDGF-BB, GM-CSF, and G-CSF) were measured using a Luminex assay, and anaphylatoxins (C3a, C4a, and C5a) were measured using Cytometric Bead Array. SCA patients in StSt showed a pro-inflammatory profile, and were indicated as being higher producers of CCL2, IL-1ß, IL-12p70, IFN-γ, IL-17A, and GM-CSF, while VOC is highlighted by molecules IL-4 and IL-5, but also IL-2, IL-7, PDGF-BB, and G-CSF. PDGF-BB and IL-1ra seemed to be two important hallmarks for the acute-to-chronic stage, due to their significant decrease after crisis inflammation and statistical difference in VOC and CV groups. These molecules show higher levels and a strong correlation with other molecules in VOC. Furthermore, they remain at higher levels even after crisis recovery, which suggest their importance in the role of inflammation during crisis and participation in immune cell adhesion and activation. These results support a relevant role of cytokines, neutrophil and monocytes, since these may act as markers of VOC inflammation in SCA patients.

Tandem P-selectin glycoprotein ligand immunoglobulin prevents lung vaso-occlusion in sickle cell disease mice.

Sickle cell disease (SCD) is a monogenic disorder estimated to affect more than three million people worldwide. Acute systemic painful vaso-occlusive episode (VOE) is the primary reason for emergency medical care among SCD patients. VOE may also progress to acute chest syndrome (ACS), a type of acute lung injury and one of the primary reasons for mortality among SCD patients. Recently, P-selectin monoclonal antibodies were found to attenuate VOE in SCD patients and lung vaso-occlusion in transgenic humanized SCD mice, highlighting the therapeutic benefit of P-selectin inhibition in SCD. Here, we use quantitative fluorescence intravital lung microscopy (qFILM) to illustrate that tandem P-selectin-glycoprotein ligand-immunoglobulin (TSGL-Ig) fusion molecule containing four P-selectin binding sites, significantly attenuated intravenous (IV) oxyhemoglobin triggered lung vaso-occlusion in SCD mice. These findings highlight the therapeutic potential of TSGL-Ig in preventing VOE and ACS in SCD.

Vascular mineralocorticoid receptor activation and disease.

Mineralocorticoid receptor activation in endothelial and smooth muscle cells can promote vascular disease by increasing oxidative stress, promoting inflammation, accelerating vascular stiffness, remodeling, and calcification, altering vessel responsiveness to various vasoactive factors, thus altering vascular tone and blood pressure, and by altering angiogenesis. Here, we review the recent evidence highlighting the impact of vascular mineralocorticoid receptor activation in pathological situations, including kidney injury, vascular injury associated with metabolic diseases, atherosclerosis, cerebral vascular injury during hypertension, vascular stiffening and aging, pulmonary hypertension, vascular calcification, cardiac remodeling, wound healing, inflammation, thrombosis, and disorders related to angiogenic defects in the eye. The possible mechanisms implicating mineralocorticoid receptor activation in various vascular disorders are discussed. Altogether, recent evidence points towards pharmacological mineralocorticoid receptor inhibition as a strategy to treat diseases in which overactivation of the mineralocorticoid receptor in endothelial and/or smooth muscle cells may play a pivotal role.

Maternal supraphysiological hypercholesterolemia associates with endothelial dysfunction of the placental microvasculature.

Maternal physiological or supraphysiological hypercholesterolemia (MPH, MSPH) occurs during pregnancy. MSPH is associated with foetal endothelial dysfunction and atherosclerosis. However, the potential effects of MSPH on placental microvasculature are unknown. The aim of this study was to determine whether MSPH alters endothelial function in the placental microvasculature both ex vivo in venules and arterioles from the placental villi and in vitro in primary cultures of placental microvascular endothelial cells (hPMEC). Total cholesterol < 280 mg/dL indicated MPH, and total cholesterol ≥280 mg/dL indicated MSPH. The maximal relaxation to histamine, calcitonin gene-related peptide and adenosine was reduced in MSPH venule and arteriole rings. In hPMEC from MSPH placentas, nitric oxide synthase (NOS) activity and L-arginine transport were reduced without changes in arginase activity or the protein levels of endothelial NOS (eNOS), human cationic amino acid 1 (hCAT-1), hCAT-2A/B or arginase II compared with hPMEC from MPH placentas. In addition, it was shown that adenosine acts as a vasodilator of the placental microvasculature and that NOS is active in hPMEC. We conclude that MSPH alters placental microvascular endothelial function via a NOS/L-arginine imbalance. This work also reinforces the concept that placental endothelial cells from the macro- and microvasculature respond differentially to the same pathological condition.

Mechanistic Role of the Calcium-Dependent Protease Calpain in the Endothelial Dysfunction Induced by MPO (Myeloperoxidase).

MPO (myeloperoxidase) is a peroxidase enzyme secreted by activated leukocytes that plays a pathogenic role in cardiovascular disease, mainly by initiating endothelial dysfunction. The molecular mechanisms of the endothelial damaging action of MPO remain though largely elusive. Calpain is a calcium-dependent protease expressed in the vascular wall. Activation of calpains has been implicated in inflammatory disorders of the vasculature. Using endothelial cells and genetically modified mice, this study identifies the µ-calpain isoform as novel downstream signaling target of MPO in endothelial dysfunction. Mouse lung microvascular endothelial cells were stimulated with 10 nmol/L MPO for 180 minutes. MPO denitrosylated µ-calpain C-terminus domain, and time dependently activated µ-calpain, but not the m-calpain isoform. MPO also reduced Thr172 AMPK (AMP-activated protein kinase) and Ser1177 eNOS (endothelial nitric oxide synthase) phosphorylation via upregulation of PP2A (protein phosphatase 2) expression. At the functional level, MPO increased endothelial VCAM-1 (vascular cell adhesion molecule 1) abundance and the adhesion of leukocytes to the mouse aorta. In MPO-treated endothelial cells, pharmacological inhibition of calpain activity attenuated expression of VCAM-1 and PP2A, and restored Thr172 AMPK and Ser1177 eNOS phosphorylation. Compared with wild-type mice, µ-calpain deficient mice experienced reduced leukocyte adhesion to the aortic endothelium in response to MPO. Our data first establish a role for calpain in the endothelial dysfunction and vascular inflammation of MPO. The MPO/calpain/PP2A signaling pathway may provide novel pharmacological targets for the treatment of inflammatory vascular disorders.

Heme-mediated cell activation: the inflammatory puzzle of sickle cell anemia.

INTRODUCTION: Hemolysis triggers the onset of several clinical manifestations of sickle cell anemia (SCA). During hemolysis, heme, which is derived from hemoglobin (Hb), accumulates due to the inability of detoxification systems to scavenge sufficiently. Heme exerts multiple harmful effects, including leukocyte activation and migration, enhanced adhesion molecule expression by endothelial cells and the production of pro-oxidant molecules. Area covered: In this review, we describe the effects of heme on leukocytes and endothelial cells, as well as the features of vascular endothelial cells related to vaso-occlusion in SCA. Expert commentary: Free Hb, heme and iron, potent cytotoxic intravascular molecules released during hemolysis, can exacerbate, modulate and maintain the inflammatory response, a main feature of SCA. Endothelial cells in the vascular environment, as well as leukocytes, can become activated via the molecular signaling effects of heme. Due to the hemolytic nature of SCA, hemolysis represents an interesting therapeutic target for heme-scavenging purposes.

Nitric Oxide is a Central Common Metabolite in Vascular Dysfunction Associated with Diseases of Human Pregnancy.

Preeclampsia (PE), gestational diabetes mellitus (GDM), and maternal supraphysiological hypercholesterolaemia (MSPH) are pregnancy-related conditions that cause metabolic disruptions leading to alterations of the mother, fetus and neonate health. These syndromes result in fetoplacental vascular dysfunction, where nitric oxide (NO) plays a crucial role. PE characterizes by abnormal increase in the placental blood pressure and a negative correlation between NO level and fetal weight, suggesting that increased NO level and oxidative stress could be involved. GDM courses with macrosomia along with altered function of the fetal cardiovascular system and fetoplacental vasculature. Even when NO synthesis in the fetoplacental vasculature is increased, NO bioavailability is reduced due to the higher oxidative stress seen in this disease. In MSPH, there is an early development of atherosclerotic lesions in fetal and newborn arteries, altered function of the fetoplacental vasculature, and higher markers of oxidative stress in fetal blood and placenta, thus, vascular alterations related with NO metabolism occur as a consequence of this syndrome. Potential mechanisms of altered NO synthesis and bioavailability result from transcriptional and post-translational NO synthases (NOS) modulation, including phosphorylation/dephosphorylation cycles, coupling/uncoupling of NOS, tetrahydrobiopterin bioavailability, calcium/calmodulin-NOS and caveolin-1-NOS interaction. Additionally, oxidative stress also plays a role in the reduced NO bioavailability. This review summarizes the available information regarding lower NO bioavailability in these pregnancy pathologies. A common NO-dependent mechanism in PE, GDM and MSPH contributing to fetoplacental endothelial dysfunction is described.