Control Of Vascular Tone Research Articles

Abstract P333: Influence Of RSK2 On Blood Pressure In Aging

Hypertension (HTN) is highly prevalent and is a significant risk factor for CVD. Excessive vasoconstriction contributes to HTN. Recently, p90 ribosomal S6 kinase, isoform 2 (RSK2) signaling has been shown to play a significant role in the regulation of basal vascular tone and BP control by phosphorylating RLC20 to promote smooth muscle contractility. Young adult Rsk2 KO mice have lower BP than WT littermates. Here, we examine the role of RSK2 in a geriatric HTN mouse model. Male >2-year old WT and Rsk2 KO mice underwent daily BP measurements using tail cuff manometry. After 2 weeks of training, baseline (BL) BP was recorded, followed by 2 weeks of HTN induced by 20 mg/kg/day of L-N G -Nitroarginine methyl ester (L-NAME) via drinking water. Echocardiographic studies were performed at BL. WT mice had significant mortality (7 of 11 died), not seen in KO (1 of 8 died). At BL, WT mice had a significantly higher SBP compared to KOs (123±10 vs. 99±12 mmHg). L-NAME elevated SBP in WT but not KO mice (137±2 vs. 97±8 mmHg). Echocardiographic studies at BL showed no differences between genotypes. However, when ejection fraction (EF) was correlated with SBP, EF was negatively correlated with SBP in WT (-0.94 %/mmHg, p = 0.046, R 2 = 0.59, n = 6) but not KO mice (p = 0.15, n = 7). Clinically, HTN-associated mortality and morbidity primarily affects older populations. Here, we show that the loss of RSK2 reduces BP in geriatric mice, similar to findings in young adult mice, and that it also abolished the hypertensive effects of L-NAME. Aged Rsk2 KO mice appear to be protected from cardiovascular effects of aging. RSK2 is a potential target for pharmacologic inhibition to treat HTN and related risks in geriatric populations.

Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria.

SummaryBackgroundIn malaria-endemic areas, subjects from specific groups like Fulani have a peculiar protection against malaria, with high levels of IgM but also frequent anaemia and splenomegaly. The mechanisms underlying this phenotype remain elusive.MethodsIn a cohort study set up in Benin, West Africa, after a careful evaluation of malaria-related phenotypes, we measured the deformability of circulating erythrocytes in genetically distinct groups (including Fulani) living in sympatry, using ektacytometry and microsphiltration, a mimic of how the spleen clears rigid erythrocytes. Heritability of erythrocytes deformability was calculated, followed by a genome-wide association study (GWAS) of the same phenotype.FindingsCompared to non-Fulani, Fulani displayed a higher deformability of circulating erythrocytes, pointing to an enhanced clearance of rigid erythrocytes by the spleen. This phenotype was observed in individuals displaying markers of Plasmodium falciparum infection. The heritability of this new trait was high, with a strong multigenic component. Five of the top 10 genes selected by a population structure-adjusted GWAS, expressed in the spleen, are potentially involved in splenic clearance of erythrocytes (CHERP, MB, PALLD, SPARC, PDE10A), through control of vascular tone, collagen synthesis and macrophage activity.InterpretationIn specific ethnic groups, genetically-controlled processes likely enhance the innate retention of infected and uninfected erythrocytes in the spleen, explaining splenomegaly, anaemia, cryptic intrasplenic parasite loads, hyper-IgM, and partial protection against malaria. Beyond malaria-related phenotypes, inherited splenic hyper-filtration of erythrocytes may impact the pathogenesis of other hematologic diseases.FundingANR, National Geographic Society, IMEA, IRD, and Région Ile-de-France.

Head hemodynamics and systemic responses during auditory stimulation.

The present study aims to analyze the systemic response to auditory stimulation by means of hemodynamic (cephalic and peripheral) and autonomic responses in a broad range of auditory intensities (70.9, 77.9, 84.5, 89.5, 94.5 dBA). This approach could help to understand the possible influence of the autonomic nervous system on the cephalic blood flow. Twenty‐five subjects were exposed to auditory stimulation while electrodermal activity (EDA), photoplethysmography (PPG), electrocardiogram, and functional near‐infrared spectroscopy signals were recorded. Seven trials with 20 individual tones, each for the five intensities, were presented. The results showed a differentiated response to the higher intensity (94.5 dBA) with a decrease in some peripheral signals such as the heart rate (HR), the pulse signal, the pulse transit time (PTT), an increase of the LFnu power in PPG, and at the head level a decrease in oxygenated and total hemoglobin concentration. After the regression of the visual channel activity from the auditory channels, a decrease in deoxyhemoglobin in the auditory cortex was obtained, indicating a likely active response at the highest intensity. Nevertheless, other measures, such as EDA (Phasic and Tonic), and heart rate variability (Frequency and time domain) showed no significant differences between intensities. Altogether, these results suggest a systemic and complex response to high‐intensity auditory stimuli. The results obtained in the decrease of the PTT and the increase in LFnu power of PPG suggest a possible vasoconstriction reflex by a sympathetic control of vascular tone, which could be related to the decrease in blood oxygenation at the head level.

The Role of Perivascular Adipose Tissue-Derived Hydrogen Sulfide in the Control of Vascular Homeostasis.

Significance: Emerging evidence suggests that perivascular adipose tissue (PVAT) has a relevant role in the control of vascular tone in physiology and pathology. Healthy PVAT has anticontractile, anti-inflammatory, and antioxidative actions. Accumulating data from both human and experimental animal models indicate that PVAT dysfunction is conceivably coupled to cardiovascular diseases, and it is associated with vascular inflammation, oxidative stress, and arterial remodeling. Therefore, "healthy" PVAT may constitute a novel therapeutic target for the prevention and treatment of cardiovascular diseases. Recent Advances: Hydrogen sulfide (H2S) has been recognized as a vascular anti-contractile factor released from PVAT. The enzymes deputed to H2S biosynthesis are variously expressed in PVAT and strictly dependent on the vascular bed and species. Metabolic and cardiovascular diseases can alter the morphological and secretory characteristics of PVAT, influencing also the H2S signaling. Here, we discuss the role of PVAT-derived H2S in healthy conditions and its relevance in alterations occurring in vascular disorders. Critical Issues: We discuss how a better understanding may help in the prevention of vascular dysfunction related to alteration in PVAT-released H2S as well as the importance of the interplay between PVAT and H2S. Future Directions: We propose future directions to evaluate the contribution of each enzyme involved in H2S biosynthesis and their alteration/switch occurring in vascular disorders and the remaining challenges in investigating the role of H2S. Antioxid. Redox Signal. 37, 84-97.

Targeting Lipid-Ion Channel Interactions in Cardiovascular Disease.

General lipid-lowering strategies exhibit clinical benefit, however, adverse effects and low adherence of relevant pharmacotherapies warrants the investigation into distinct avenues for preventing dyslipidemia-induced cardiovascular disease. Ion channels play an important role in the maintenance of vascular tone, the impairment of which is a critical precursor to disease progression. Recent evidence suggests that the dysregulation of ion channel function in dyslipidemia is one of many contributors to the advancement of cardiovascular disease thus bringing to light a novel yet putative therapeutic avenue for preventing the progression of disease mechanisms. Increasing evidence suggests that lipid regulation of ion channels often occurs through direct binding of the lipid with the ion channel thereby creating a potential therapeutic target wherein preventing specific lipid-ion channel interactions, perhaps in combination with established lipid lowering therapies, may restore ion channel function and the proper control of vascular tone. Here we first detail specific examples of lipid-ion channel interactions that promote vascular dysfunction and highlight the benefits of preventing such interactions. We next discuss the putative therapeutic avenues, such as peptides, monoclonal antibodies, and aspects of nanomedicine that may be utilized to prevent pathological lipid-ion channel interactions. Finally, we discuss the experimental challenges with identifying lipid-ion channel interactions as well as the likely pitfalls with developing the aforementioned putative strategies.

Mitochondrial oxidative phosphorylation fuels endothelial control of blood vessel tone

Arteries and veins are lined by non‐proliferating endothelial cells that play a critical role in regulating blood flow. Endothelial cells also regulate tissue perfusion, metabolite exchange, and thrombosis. It is thought that endothelial cells rely on ATP generated via glycolysis to fuel each of these energy‐demanding processes. However, endothelial metabolism has mainly been studied in the context of proliferative cells in angiogenesis, and little is known about energy production in endothelial cells within the fully‐formed vascular wall.Using intact arteries isolated from rats and mice, we show that inhibiting mitochondrial oxidative phosphorylation at mitochondrial complex V disrupts calcium‐dependent, nitric oxide‐mediated endothelial cell control of vascular tone. Basal, mechanically‐activated, and agonist‐evoked calcium activity in intact artery endothelial cells are each prevented by inhibiting mitochondrial ATP synthesis. This effect is mimicked by blocking the transport of pyruvate, the master fuel for mitochondrial energy production, through the mitochondrial pyruvate carrier. The role for endothelial cell energy production is independent of species, sex, or vascular bed.These data show that mitochondrial ATP is necessary for the obligatory role of endothelial cells in the control of blood vessel diameter, and validate the idea of targeting endothelial cell metabolism to treat endothelial cell dysfunction in cardiovascular disease.

Potential Effects of Natural H2S-Donors in Hypertension Management.

After the discovery of hydrogen sulfide (H2S) in the central nervous system by Abe and Kimura in 1996, the physiopathological role of H2S has been widely investigated in several systems such as the cardiovascular. In particular, H2S plays a pivotal role in the control of vascular tone, exhibiting mechanisms of action able to induce vasodilation: for instance, activation of potassium channels (KATP and Kv7) and inhibition of 5-phosphodiesterase (5-PDE). These findings paved the way for the research of natural and synthetic exogenous H2S-donors (i.e., molecules able to release H2S) in order to have new tools for the management of hypertension. In this scenario, some natural molecules derived from Alliaceae (i.e., garlic) and Brassicaceae (i.e., rocket or broccoli) botanical families show the profile of slow H2S-donors able to mimic the endogenous production of this gasotransmitter and therefore can be viewed as interesting potential tools for management of hypertension or pre-hypertension. In this article, the preclinical and clinical impacts of these natural H2S-donors on hypertension and vascular integrity have been reviewed in order to give a complete panorama of their potential use for the management of hypertension and related vascular diseases.

Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice.

The nitric oxide–guanylyl cyclase-1–cyclic guanylate monophosphate (NO–GC-1–cGMP) pathway is integral to the control of vascular tone and morphology. Mice lacking the alpha catalytic domain of guanylate cyclase (GC1−/−) develop retinal ganglion cell (RGC) degeneration with age, with only modest fluctuations in intraocular pressure (IOP). Increasing the bioavailability of cGMP in GC1−/− mice prevents neurodegeneration independently of IOP, suggesting alternative mechanisms of retinal neurodegeneration. In continuation to these studies, we explored the hypothesis that dysfunctional cGMP signaling leads to changes in the neurovascular unit that may contribute to RGC degeneration. We assessed retinal vasculature and astrocyte morphology in young and aged GC1−/− and wild type mice. GC1−/− mice exhibit increased peripheral retinal vessel dilation and shorter retinal vessel branching with increasing age compared to Wt mice. Astrocyte cell morphology is aberrant, and glial fibrillary acidic protein (GFAP) density is increased in young and aged GC1−/− mice, with areas of dense astrocyte matting around blood vessels. Our results suggest that proper cGMP signaling is essential to retinal vessel morphology with increasing age. Vascular changed are preceded by alterations in astrocyte morphology which may together contribute to retinal neurodegeneration and loss of visual acuity observed in GC1−/− mice.

A multiscale model of the cardiovascular system that incorporates baroreflex control of chronotropism, cell-level contractility, and vascular tone

Multiscale models of the cardiovascular system can provide new insights into physiological and pathological processes. Models that incorporate molecular-level effects may be particularly useful for clinical applications because they can predict the functional consequences of pharmaceuticals that modulate the properties of molecules and/or the rate at which they undergo reactions. PyMyoVent is a computer model that bridges from molecular to organ-level function and simulates a left ventricle pumping blood through the systemic circulation (https://campbell-muscle-lab.github.io/PyMyoVent/).

Adrenergic receptors gene polymorphisms and autonomic nervous control of heart and vascular tone.

Adrenergic receptors (ARs) are the primary targets of catecholamines released from the sympathetic nerve endings during their activation. ARs play a central role in autonomic nervous system and serve as important targets of widely used drugs. Several ARs gene polymorphisms were found to be associated with cardiovascular disease in previous clinical studies. Although more precise mechanism of the polymorphisms influence on autonomic control of cardiovascular system was studied in many previous physiological studies, their results are not unequivocal. This paper reviews the results of clinical and physiological studies focused on the impact of selected common single nucleotide polymorphisms of ARs genes involved in sympathetic control on cardiovascular system and its control. In summary, many studies assessed only a very limited range of cardiovascular control related parameters providing only very limited view on the complex cardiovascular control. The overview of partially contradicting results underlines a need to examine wider range of cardiovascular measures including their reactivity under various stress conditions requiring further study. It is expected that an effect of one given polymorphism is not very prominent, but it is suggested that even subtle differences in cardiovascular control could - on a longer time scale - lead to the development of severe pathological consequences.

Polymodal Control of TMEM16x Channels and Scramblases.

The TMEM16A/anoctamin-1 calcium-activated chloride channel (CaCC) contributes to a range of vital functions, such as the control of vascular tone and epithelial ion transport. The channel is a founding member of a family of 10 proteins (TMEM16x) with varied functions; some members (i.e., TMEM16A and TMEM16B) serve as CaCCs, while others are lipid scramblases, combine channel and scramblase function, or perform additional cellular roles. TMEM16x proteins are typically activated by agonist-induced Ca2+ release evoked by Gq-protein-coupled receptor (GqPCR) activation; thus, TMEM16x proteins link Ca2+-signalling with cell electrical activity and/or lipid transport. Recent studies demonstrate that a range of other cellular factors—including plasmalemmal lipids, pH, hypoxia, ATP and auxiliary proteins—also control the activity of the TMEM16A channel and its paralogues, suggesting that the TMEM16x proteins are effectively polymodal sensors of cellular homeostasis. Here, we review the molecular pathophysiology, structural biology, and mechanisms of regulation of TMEM16x proteins by multiple cellular factors.

Spectral analysis of signals of autonomic regulation of blood circulation in patients with COVID-19 and arterial hypertension

The work aims to carry out a comparative analysis of the spectral indices of the photoplethysmogram signals and RR-intervals of healthy volunteers, patients with COVID-19, as well as patients with COVID-19 and chronic arterial hypertension of 1-2 degrees. The study included 45 records of pairs of electrocardiogram and photoplethysmogram signals. Each sample included 15 pairs of 20-minute experimental signals. The study revealed an increase in the integrated power of the low-frequency (LF) band over the integrated power of the high-frequency (HF) band in the photoplethysmogram signals in patients with COVID-19, burdened with hypertension. In the signals of the RR-intervals, the largest values of the ratio of the LF to HF indices are associated with patients without cardiovascular diseases. In turn, this may be an indicator of the different effects of viral infection and arterial hypertension on the loops of autonomic control of heart rate and vascular tone.

Aging Affects KV7 Channels and Perivascular Adipose Tissue-Mediated Vascular Tone.

Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, and QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography and membrane potential measurements with sharp electrodes. We also performed bulk RNA sequencing and quantitative reverse transcription-polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3–5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, KV7.3–5 channels represent a promising target in cardiovascular aging.

Endothelial TrkB receptor activation controls vascular tone of rat middle cerebral artery

Little is known on the cerebrovascular BDNF (brain-derived neurotrophic factor)/TrkB (tropomyosin related kinase B) pathway. This study investigated the contribution of endogenous endothelial BDNF to the control of vascular tone of rat middle cerebral artery (MCA) and the capacity of exogenous agonist of TrkB receptors to induce their relaxation. Endothelial cells constitutively expressed both BDNF and activated TrkB receptors. Supporting endothelial BDNF as an autocrine regulator of basal myogenic tone, incubation of MCA with the TrkB antagonist cyclotraxin B induced contraction as observed with incubation in the presence of inhibitors of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) production. Exposure of MCA with the TrkB agonist LM22A-4 that increased expression of TrkB receptors phosphorylated at tyrosine 816 induced relaxation of preconstricted MCA (EC50 6.7 × 10−8 mol/L) as efficiently than acetylcholine (EC50 5.3 × 10−8 mol/L). Finally, endothelium removal, exposure to a TrkB antagonist or to inhibitors of NO and EDHF production prevented the relaxant effect of LM22A-4. In conclusion, our study identified endothelial BDNF as a new autocrine regulator of vascular tone of MCA, thus making the endothelial BDNF/TrkB pathway an attractive target for strategies aiming to improve blood supply to the brain.

Placental Ischemia Says “NO” to Proper NOS-Mediated Control of Vascular Tone and Blood Pressure in Preeclampsia

In this review, we first provide a brief overview of the nitric oxide synthase (NOS) isoforms and biochemistry. This is followed by describing what is known about NOS-mediated blood pressure control during normal pregnancy. Circulating nitric oxide (NO) bioavailability has been assessed by measuring its metabolites, nitrite (NO2) and/or nitrate (NO3), and shown to rise throughout normal pregnancy in humans and rats and decline postpartum. In contrast, placental malperfusion/ischemia leads to systemic reductions in NO bioavailability leading to maternal endothelial and vascular dysfunction with subsequent development of hypertension in PE. We end this article by describing emergent risk factors for placental malperfusion and ischemic disease and discussing strategies to target the NOS system therapeutically to increase NO bioavailability in preeclamptic patients. Throughout this discussion, we highlight the critical importance that experimental animal studies have played in our current understanding of NOS biology in normal pregnancy and their use in finding novel ways to preserve this signaling pathway to prevent the development, treat symptoms, or reduce the severity of PE.

Synchronization Of Autonomic Control Loops Of Blood Circulation In Patients With COVID-19

This study aims to investigate the strength of synchronization between the autonomic control loops of the cardiovascular system (CVS) in patients with COronaVIrus Disease 2019 (COVID-19). Methods — We calculated the total percent of phase synchronization index (S index) between the loops of autonomic control of heart rate and vascular tone in two sample groups: healthy individuals and COVID-19 patients. Results — The group-average value of the S index in COVID-19 patients is lower comparing to healthy individuals, the Mann-Whitney U-test confirmed that the differences are statistically significant. Conclusion — Obtained results suggest that the decreased value of the S index reflects the presence of a viral disease, and the S index is a promising basis for non-invasive screening diagnostics of viral diseases, particularly of COVID-19.

ET-CORM Mediated Vasorelaxation of Small Mesenteric Arteries: Involvement of Kv7 Potassium Channels.

Although the vasoactive properties of carbon monoxide (CO) have been extensively studied, the mechanism by which CO mediates vasodilation is not completely understood. Through-out published studies on CO mediated vasodilation there is inconsistency on the type of K+-channels that are activated by CO releasing molecules (CORMs). Since the vasorelaxation properties of enzyme triggered CORMs (ET-CORMs) have not been studied thus far, we first assessed if ET-CORMs can mediate vasodilation of small mesenteric arteries and subsequently addressed the role of soluble guanylate cyclase (sGC) and that of K-channels herein. To this end, 3 different types of ET-CORMs that either contain acetate (rac-1 and rac-4) or pivalate (rac-8) as ester functionality, were tested ex vivo on methoxamine pre-contracted small rat mesenteric arteries in a myograph setting. Pre-contracted mesenteric arteries strongly dilated upon treatment with both types of acetate containing ET-CORMs (rac-1 and rac-4), while treatment with the pivalate containing ET-CORM (rac-8) resulted in no vasodilation. Pre-treatment of mesenteric arteries with the sGC inhibitor ODQ abolished rac-4 mediated vasodilation, similar as for the known sGC activator SNP. Likewise, rac-4 mediated vasodilation did not occur in KCL pretreated mesenteric arteries. Although mesenteric arteries abundantly expressed a variety of K+-channels only Kv7 channels were found to be of functional relevance for rac-4 mediated vasodilation. In conclusion the current results identified Kv7 channels as the main channel by which rac-4 mediates vasodilation. In keeping with the central role of Kv7 in the control of vascular tone and peripheral resistance these promising ex-vivo data warrant further in vivo studies, particularly in models of primary hypertension or cardiac diseases, to assess the potential use of ET-CORMs in these diseases.

The Endothelial Glycocalyx as a Double-Edged Sword in Microvascular Homeostasis and Pathogenesis.

Expressed on the endothelial cell (EC) surface of blood vessels, the glycocalyx (GCX), a mixture of carbohydrates attached to proteins, regulates the access of cells and molecules in the blood to the endothelium. Besides protecting endothelial barrier integrity, the dynamic microstructure of the GCX confers remarkable functions including mechanotransduction and control of vascular tone. Recently, a novel perspective has emerged supporting the pleiotropic roles of the endothelial GCX (eGCX) in cardiovascular health and disease. Because eGCX degradation occurs in certain pathological states, the circulating levels of eGCX degradation products have been recognized to have diagnostic or prognostic values. Beyond their biomarker roles, certain eGCX fragments serve as pathogenic factors in disease progression. Pharmacological interventions that attenuate eGCX degradation or restore its integrity have been sought. This review provides our current understanding of eGCX structure and function across the microvasculature in different organs. We also discuss disease or injury states, such as infection, sepsis and trauma, where eGCX dysfunction contributes to severe inflammatory vasculopathy.

AB0081 ENDOTHELIAL MARKERS WITH DYSREGULATION IN SYSTEMIC LUPUS ERYTHEMATOSUS: A SYSTEMATIC LITERATURE REVIEW

Background:Systemic lupus erythematosus (SLE) is a severe, lifelong autoimmune disease known for its multisystem organ involvement. SLE patients are known to be at risk for premature atherosclerosis at a relatively young age (1). Endothelial dysregulation is one of the pathophysiologic mechanisms that can lead to the higher risk for cardiovascular disease in SLE (2). Multiple endothelial markers with dysregulation in SLE have been described so far, of which some are associated with disease activity.Objectives:To report a systematic literature review regarding endothelial markers that are dysregulated in SLE and search for associations with disease activity.Methods:The search was performed according to the Preferred Reporting Items for Systematic review and Meta-analysis Protocols (PRISMA-P) 2015 (3). In July 2020, the search terms were used in Embase, MEDLINE, Web of Science, Google Scholar and Cochrane. Inclusion criteria were 1) published studies after the year 2000 that reported measurements of endothelial cell markers in serum and/or plasma of SLE patients (diagnosed according to ACR/SLICC criteria), 2) English language peer reviewed articles and 3) disease activity measurement (i.e. SLEDAI, BILAG, SLAM, ECLAM or PGA). Exclusion criteria were 1) case reports or editorials, 2) studies performed in animals and 3) studies with microRNA/cytokine biomarkers. There was no minimum count for study population. The screening process is shown in figure 1.Results:From 1892 hits, we identified 110 eligible articles. Table 1 shows an overview of the most frequently studied endothelial markers. These identified endothelial markers are involved in endothelial cell (EC) activation, EC apoptosis, disturbed angiogenesis, defective vascular tone control, immune dysregulation and coagulopathy. In most studies, dysregulation of the endothelial marker was associated with disease activity. The majority of the studies had a cross-sectional design, longitudinal data on endothelial markers in SLE are scarce.Conclusion:We identified multiple endothelial markers that are dysregulated in SLE and this dysregulation was often associated with disease activity in cross-sectional studies. Our future plan is to test the identified endothelial markers in (longitudinally collected) samples of (childhood onset) SLE patients, disease- and healthy controls. This will be a next step in unravelling the pathophysiology of premature atherosclerosis and cardiovascular events in SLE-patients in young adulthood.Figure 1.

Enhanced Nitrite-Mediated Relaxation of Placental Blood Vessels Exposed to Hypoxia Is Preserved in Pregnancies Complicated by Fetal Growth Restriction.

Nitric oxide (NO) is essential in the control of fetoplacental vascular tone, maintaining a high flow−low resistance circulation that favors oxygen and nutrient delivery to the fetus. Reduced fetoplacental blood flow is associated with pregnancy complications and is one of the major causes of fetal growth restriction (FGR). The reduction of dietary nitrate to nitrite and subsequently NO may provide an alternative source of NO in vivo. We have previously shown that nitrite induces vasorelaxation in placental blood vessels from normal pregnancies, and that this effect is enhanced under conditions of hypoxia. Herein, we aimed to determine whether nitrite could also act as a vasodilator in FGR. Using wire myography, vasorelaxant effects of nitrite were assessed on pre-constricted chorionic plate arteries (CPAs) and veins (CPVs) from normal and FGR pregnancies under normoxic and hypoxic conditions. Responses to the NO donor, sodium nitroprusside (SNP), were assessed in parallel. Nitrate and nitrite concentrations were measured in fetal plasma. Hypoxia significantly enhanced vasorelaxation to nitrite in FGR CPAs (p < 0.001), and in both normal (p < 0.001) and FGR (p < 0.01) CPVs. Vasorelaxation to SNP was also potentiated by hypoxia in both normal (p < 0.0001) and FGR (p < 0.01) CPVs. However, compared to vessels from normal pregnancies, CPVs from FGR pregnancies showed significantly lower reactivity to SNP (p < 0.01). Fetal plasma concentrations of nitrate and nitrite were not different between normal and FGR pregnancies. Together, these data show that nitrite-mediated vasorelaxation is preserved in FGR, suggesting that interventions targeting this pathway have the potential to improve fetoplacental blood flow in FGR pregnancies.