Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE

The accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated τ proteins in the brain are the hallmarks of Alzheimer’s disease (AD). Much of the research into the pathogenesis of AD has focused on the amyloid or τ hypothesis. These hypotheses propose that Aβ or τ aggregation is the inciting event in AD that leads to downstream neurodegeneration, inflammation, brain atrophy and cognitive impairment. Multiple drugs have been developed and are effective in preventing the accumulation and/or clearing of Aβ or τ proteins. However, clinical trials examining these therapeutic agents have failed to show efficacy in preventing or slowing the progression of the disease. Thus, there is a need for fresh perspectives and the evaluation of alternative therapeutic targets in this field. Epidemiology studies have revealed significant overlap between cardiovascular and cerebrovascular risk factors such as hypertension, diabetes, atherosclerosis and stroke to the development of cognitive impairment. This strong correlation has given birth to a renewed focus on vascular contributions to AD and related dementias. However, few genes and mechanisms have been identified. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that plays a complex role in hypertension, autoregulation of cerebral blood flow and blood–brain barrier (BBB) integrity. Multiple human genome-wide association studies have linked mutations in the cytochrome P450 (CYP) 4A (CYP4A) genes that produce 20-HETE to hypertension and stroke. Most recently, genetic variants in the enzymes that produce 20-HETE have also been linked to AD in human population studies. This review examines the emerging role of 20-HETE in AD and related dementias.

Dysregulation of the Renin-Angiotensin-Aldosterone System (RAA) in Patients Infected with SARS-CoV-2-Possible Clinical Consequences

SARS-CoV-2 impairs the renin-angiotensin-aledosterone system via binding ACE2 enzyme. ACE2 plays a key role in the biosynthesis of angiotensin (1-7), catalyzing the conversion of angiotensin 2 into angiotensin (1-7) and the reaction of angiotensin synthesis (1-9), from which angiotensin is (1-7) produced under the influence of ACE (Angiotensin-Converting Enzyme). Angiotensin 2 is a potent vasoconstrictor and atherogenic molecule converted by ACE2 to reducing inflammation and vasodilating in action angiotensin (1-7). Angiotensin (1-9), that is a product of angiotensin 1 metabolism and precursor of angiotensin (1-7), also exerts cell protective properties. Balance between angiotensin 2 and angiotensin (1-7) regulates blood pressure and ACE2 plays a critical role in this balance. ACE2, unlike ACE, is not inhibited by ACE inhibitors at the doses used in humans during the treatment of arterial hypertension. Membrane ACE2 is one of the receptors that allows SARS-CoV-2 to enter the host cells. ACE2 after SARS-CoV-2 binding is internalized and degraded. Hence ACE2 activity on the cell surface is reduced leading to increase the concentration of angiotensin 2 and decrease the concentration of angiotensin (1-7). Disturbed angiotensins metabolism, changes in ratio between angiotensins with distinct biological activities leading to domination of atherogenic angiotensin 2 can increase the damage to the lungs.

Leg heat therapy improves perceived physical function but does not enhance walking capacity or vascular function in patients with peripheral artery disease

This is the first sham-controlled study to investigate the effects of leg heat therapy (HT) on walking performance, vascular function, and quality of life in patients with peripheral artery disease (PAD). Adherence to HT was high, and the treatment was well tolerated. Our findings revealed that HT applied with water-circulating trousers evokes a clinically meaningful increase in perceived physical function and reduces the serum concentration of the potent vasoconstrictor endothelin-1 in patients with PAD.

Periodic Assessment of Antenatal and Post Natal Serum Endothelin-1 (ET-1) and Nitric Oxide (NO) Levels in Hypertensive Disorders of Pregnancy (HDP)

Hypertensive Disorders of Pregnancy (HDP) is an independent risk factor of cardiovascular (CVS) disease with endothelial dysfunction postulated to be the pathophysiology. Endothelin-1 (ET-1), a potent vasoconstrictor, has been identified as a pivotal mediator in HDP. Disturbances in nitric oxide (NO) bioavailability found in endothelial dysfunction may increase susceptibility to cardiovascular diseases such as hypertension. The study aims to determine serial ET-1 and NO levels in patients with HDP and its role in persistent endothelial dysfunction. Thirty-six pregnant women from the following categories (i) normal pregnant women (Control) (ii) chronic hypertension during pregnancy (CH) and (iii) pregnancy induced hypertension (PIH) participated in this study. Blood pressure indices measurements and sample collection were done at antepartum (32 weeks) and postpartum (8 weeks and 12 weeks). ET-1 and serum NO were measured using the Human ET-1 (Endothelin-1) ELISA Kit and Nitric Oxide (total) detection kit respectively. Results: Serum ET-1 was significantly higher in patients with CH (55.3 pg/ml) and PIH (35.6 pg/ml) compared to Control (11.8 pg/ml) during antenatal until 3 months postpartum (CH 38.3 pg/ml, PIH 29.5 pg/ml, Control 1.9 pg/ml). This was accompanied by significantly lower levels of serum NO in HDP patients. Persistently higher than normal levels of ET-1 and lower than normal levels of NO up to 3 months postpartum in patients with history of HDP indicate presence of persistent endothelial dysfunction despite BP normalisation in PIH patients. Long term NO/ET-1 imbalance may account for the increased CVS disease risk.

Intravascular Endothelin-1 does not trigger or increase susceptibility to Spreading Depolarizations

Objectives Spreading depolarizations (SD) likely manifest as aura in migraineurs. Triggers are unknown although vascular events have been implicated. Direct carotid puncture has been reported to trigger migraine with aura. The potent vasoconstrictor endothelin-1 (ET-1), which can be released from the endothelium under pathological conditions, may play a role. Here, we tested whether intracarotid ET-1 infusion triggers SD and whether systemic ET-1 infusion increases the susceptibility to SD. Methods Carotid infusions were performed in mice (C57BL/6, male) through a catheter placed at the carotid bifurcation via the external carotid artery. Intracarotid ET-1 (1.25 nmol/ml) was infused at various rates (2–16 μl/min) with or without heparin in the catheter and compared with vehicle infusion (PBS with 0.01% acetic acid) or sham-operated mice (n = 5). Systemic infusions ET-1 (1 nmol/kg, n = 7) or vehicle (n = 7) infusions were performed in rats (Sprague-Dawley, male) via the tail vein. Electrical SD threshold and KCl-induced SD frequency were measured after the infusion. Results Intracarotid infusion of saline (n = 19), vehicle (n = 7) or ET-1 (n = 12) all triggered SDs at various proportions (21%, 14% and 50%, respectively). These were often associated with severe hypoperfusion prior to SD onset. Heparinizing the infusion catheter completely prevented SD occurrence during the infusions (n = 8), implicating microembolization from carotid thrombi as the trigger. Sham-operated mice never developed SD. Systemic infusion of ET-1 did not affect the electrical SD threshold or KCl-induced SD frequency. Conclusion Intravascular ET-1 does not trigger or increase susceptibility to SD. Microembolization was the likely trigger for migraine auras in patients during carotid puncture.

Endothelin-1-induced endothelial microvesicles impair endothelial cell function

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide released by the endothelium that contributes to the regulation of vascular tone. Overexpression of ET-1 has been implicated in the etiology of atherosclerotic vascular disease. Endothelial cell-derived microvesicles (EMVs) play a pivotal role in vascular health and disease. Their functional phenotype is largely dictated by the stimulus for release. EMVs released in response to various pathological conditions have been shown to elicit deleterious vascular effects. In the present study, we determined, in vitro, the effect of ET-1 on EMV release from endothelial cells and the effects of ET-1-generated EMVs on endothelial cell inflammation, apoptosis, and endothelial nitric oxide synthase (eNOS). ET-1 induced a marked increase in EMV release. ET-1-generated EMVs significantly increased endothelial cell inflammation and reduced eNOS protein expression and activation. Moreover, the endothelial effects of ET-1-derived EMVs were similar to the direct effects of ET-1. ET-1-generated EMVs may contribute to the proatherogenic profile of ET-1.

Roles of angiotensin II as vasopressor in vasodilatory shock

Shock is an acute condition of circulatory failure resulting in life-threatening organ dysfunction, high morbidity and high mortality. Current management includes fluid and catecholamine therapy to maintain adequate mean arterial pressure and organ perfusion. Norepinephrine is recommended as first-line vasopressor, but other agents are available. Angiotensin II is an alternative potent vasoconstrictor without chronotropic or inotropic properties. Several studies, including a large randomized controlled trial have demonstrated its ability to increase blood pressure with catecholamine-sparing effects. Angiotensin II was consequently approved by the US FDA in 2017 and the EU in 2019 as an add-on vasopressor in vasodilatory shock. This review aims to discuss its basic pharmacology, clinical efficacy, safety and future perspectives.

Association between Plasma Urotensin II and Risk of Hypertension: Findings from a Prospective Study

Up to date, human urotensin II (UII) is the most potent vasoconstrictor in mammalian animals. To explore whether UII played an important role in the development of hypertension, we conducted a prospective study in Changshu city, China. The baseline investigation was carried out in 2007, and the first follow-up investigation was conducted in 2013. From the participants, we randomly obtained 2000 normotensive subjects aged 40 years and older without any severe disease at baseline and examined plasma UII and endothelin-1 (ET-1) with their blood samples at baseline. Logistic models were used to analyze the association between baseline UII, baseline ET-1, and newly occurring hypertension. In 1,819 subjects with complete data, 723 subjects developed into hypertensive in about five years. After adjusting some potential confounders, the odds ratio (95% confidence interval) for risk of hypertension comparing the highest with the lowest quartile of baseline UII was 0.888 (0.689–1.144). The role of UII in the development of hypertension was not found in the current study; therefore, further research studies should be conducted to explore the relationship between UII and hypertension.

Acute and delayed nephropathy due to methamphetamine abuse

Methamphetamine is a highly addictive drug that acts as a stimulant for the central nervous system. It increases alertness and physical activity but can cause cardiac dysrhythmias, hypertension, hallucinations and violent behavior. The excretion rate of methamphetamine by the kidney can be seriously altered by urinary pH. Methamphetamine is a weak base, consequently, the proportion of the excreted amount of unchanged drug can vary from as little as 2% in alkaline (pH ≥8.0) to 76% in acidic urine (pH ≤5.0). Methamphetamine is metabolized by hepatic metabolism and renal excretion via cytochrome P450 2D6 (CYP2D6). The effects of methamphetamine on the kidneys can be divided into the following sub-groups: vascular effects, non-traumatic rhabdomyolysis and direct nephrotoxicity. Additionally, methamphetamine directly stimulates the release of ET-1, a potent vasoconstrictor. ET-1 stimulates vasoconstriction, inflammation and fibrosis in kidney, thus promoting hypertension, atherosclerosis and chronic kidney disease.

Cerebrovascular effects of endothelin-1 investigated using high-resolution magnetic resonance imaging in healthy volunteers

Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide released from vascular endothelium. ET-1 plays a major role in cerebrovascular disorders and likely worsens the outcome of acute ischaemic stroke and aneurismal subarachnoid haemorrhage through vasoconstriction and cerebral blood flow (CBF) reduction. Disorders that increase the risk of stroke, including hypertension, diabetes mellitus, and acute myocardial infarction, are associated with increased plasma levels of ET-1. The in vivo human cerebrovascular effects of systemic ET-1 infusion have not previously been investigated. In a two-way crossover, randomized, double-blind design, we used advanced 3 tesla MRI methods to investigate the effects of high-dose intravenous ET-1 on intra- and extracranial artery circumferences, global and regional CBF, and cerebral metabolic rate of oxygen (CMRO2) in 14 healthy volunteers. Following ET-1 infusion, we observed a 14% increase of mean arterial blood pressure, a 5% decrease of middle cerebral artery (MCA) circumference, but no effects on extracerebral arteries and no effects on CBF or CMRO2. Collectively, the findings indicate MCA constriction secondarily to blood pressure increase and not due to a direct vasoconstrictor effect of ET-1. We suggest that, as opposed to ET-1 in the subarachnoid space, intravascular ET-1 does not exert direct cerebrovascular effects in humans.