Vascular Structural Alterations Research Articles

Sestrin2 Restricts Endothelial-to-Mesenchymal Transition Induced by Lipolysaccharide via Autophagy.

Endothelial-to-mesenchymal transition (EndoMT) is a significant biological phenomenon wherein endothelial cells undergo a loss of their endothelial traits and progressively acquire mesenchymal characteristics. Consequently, this transformation leads to both a compromised ability to maintain lumen permeability and alterations in vascular structure, which hampers the preservation of blood-brain barrier integrity. This study aimed to investigate inflammation-induced EndoMT and its etiology, with the goal of impeding the infiltration of peripheral inflammation into the central nervous system. Lipolysaccharide (LPS) was administered intraperitoneally to mice several times to establish a chronic inflammatory model. A cellular inflammatory model was established by LPS in human brain microvascular endothelial cells (HBMECs). The mRNA expressions of inflammatory cytokines interleukin-1β (IL-1β) and IL-6 were detected by real-time polymerase chain reaction (PCR). Immunofluorescence staining of platelet endothelial cell adhesion molecule-1 (CD31) and alpha smooth muscle actin (α-SMA) was conducted to assess the level of EndoMT. The expression levels of Occludin, zona occludens protein 1 (ZO-1), Sestrin2, microtubule-associated protein1 light chain 3 (LC3) and inducible nitric oxide synthase (iNOS) were detected by western blotting. LPS treatment induced the downregulation of ZO-1 and Occludin, which was accompanied by the elevated expressions of iNOS, α-SMA, Sestrin2 and LC3-II in the mouse cortex and HBMECs. Mechanistically, the knockdown of Sestrin2 in HBMECs exacerbated the EndoMT induced by LPS treatment, while the overexpression of Sestrin2 inhibited this process. Moreover, the induction of autophagy by rapamycin rescued the EndoMT induced by Sestrin2 knockdown. This study revealed that Sestrin2 inhibited endothelial inflammation and EndoMT via enhanced autophagy, which may provide a potential drug target for cerebrovascular inflammatory injury.

Early remodeling and loss of light-induced dilation of retinal small arteries in CADASIL

A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1–2 μm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity.

Aberrant vascular architecture in the hippocampus correlates with tau burden in mild cognitive impairment and Alzheimer’s disease

Cerebrovascular dysfunction is a significant contributor to Alzheimer’s disease (AD) progression. AD mouse models show altered capillary morphology, density, and diminished blood flow in areas of tau and beta-amyloid accumulation. The purpose of this study was to examine alterations in vascular structure and their contributions to perfusion deficits in the hippocampus in AD and mild cognitive impairment (MCI). Seven individuals with AD and MCI (1 AD/6 MCI), nine cognitively intact older healthy adults, and seven younger healthy adults underwent pseudo-continuous arterial spin labeling (PCASL) and gradient-echo/spin-echo (GESE) dynamic susceptibility contrast (DSC) MRI. Cerebral blood flow (CBF), cerebral blood volume, relative vessel size index (rVSI), and mean vessel density were calculated from model fitting. Lower CBF from PCASL and SE DSC MRI was observed in the hippocampus of AD/MCI group. rVSI in the hippocampus of the AD/MCI group was larger than that of the two healthy groups (FDR-P = 0.02). No difference in vessel density was detected between the groups. We also explored relationship of tau burden from 18F-flortaucipir positron emission tomography and vascular measures from MRI. Tau burden was associated with larger vessel size and lower CBF in the hippocampus. We postulate that larger vessel size may be associated with vascular alterations in AD/MCI.

Vascular deficits contributing to skeletal fragility in type 1 diabetes.

Over 1 million Americans are currently living with T1D and improvements in diabetes management have increased the number of adults with T1D living into later decades of life. This growing population of older adults with diabetes is more susceptible to aging comorbidities, including both vascular disease and osteoporosis. Indeed, adults with T1D have a 2- to 3- fold higher risk of any fracture and up to 7-fold higher risk of hip fracture compared to those without diabetes. Recently, diabetes-related vascular deficits have emerged as potential risks factors for impaired bone blood flow and poor bone health and it has been hypothesized that there is a direct pathophysiologic link between vascular disease and skeletal outcomes in T1D. Indeed, microvascular disease (MVD), one of the most serious consequences of diabetes, has been linked to worse bone microarchitecture in older adults with T1D compared to their counterparts without MVD. The association between the presence of microvascular complications and compromised bone microarchitecture indicates the potential direct deleterious effect of vascular compromise, leading to abnormal skeletal blood flow, altered bone remodeling, and deficits in bone structure. In addition, vascular diabetic complications are characterized by increased vascular calcification, decreased arterial distensibility, and vascular remodeling with increased arterial stiffness and thickness of the vessel walls. These extensive alterations in vascular structure lead to impaired myogenic control and reduced nitric-oxide mediated vasodilation, compromising regulation of blood flow across almost all vascular beds and significantly restricting skeletal muscle blood flow seen in those with T1D. Vascular deficits in T1D may very well extend to bone, compromising skeletal blood flow control, and resulting in reduced blood flow to bone, thus negatively impacting bone health. Indeed, several animal and ex vivo human studies report that diabetes induces microvascular damage within bone are strongly correlated with diabetes disease severity and duration. In this review article, we will discuss the contribution of diabetes-induced vascular deficits to bone density, bone microarchitecture, and bone blood flow regulation, and review the potential contribution of vascular disease to skeletal fragility in T1D.

Alamandine attenuates oxidative stress in the right carotid following transverse aortic constriction in mice

ObjectivePressure overload can result in significant changes to the structure of blood vessels, a process known as vascular remodeling. High levels of tension can cause vascular inflammation, fibrosis, and structural alterations to the vascular wall. Prior research from our team has demonstrated that the oral administration of alamandine can promote vasculoprotective effects in mice aorta that have undergone transverse aortic constriction (TAC). Furthermore, changes in local hemodynamics can affect the right and left carotid arteries differently after TAC. Thus, in this study, we aimed to assess the effects of alamandine treatment on right carotid remodeling and the expression of oxidative stress-related substances induced by TAC. Methods and resultsMale C57BL/6 mice were categorized into three groups: Sham, TAC, and TAC treated with alamandine (TAC+ALA). Alamandine treatment was administered orally by gavage (30 µg/kg/day), starting three days before the surgery, and continuing for a period of fourteen days. Morphometric analysis of hematoxylin and eosin-stained sections revealed that TAC induced hypertrophic and positive remodeling in the right carotid artery. Picrosirius Red staining also demonstrated an increase in total collagen deposition in the right carotid artery due to TAC-induced vascular changes. Alamandine treatment effectively prevented the increase in reactive oxygen species production and depletion of nitric oxide levels, which were induced by TAC. Finally, alamandine treatment was also shown to prevent the increased expression of nuclear factor erythroid 2-related factor 2 and 3-nitrotyrosine that were induced by TAC. ConclusionOur results suggest that alamandine can effectively attenuate pathophysiological stress in the right carotid artery of animals subjected to TAC.

Vascular Effects, Potential Pathways and Mediators of Fetal Exposure to Alcohol and Cigarette Smoking during Pregnancy: A Narrative Review.

(1) Background: Programming of atherosclerosis results in vascular structure and function alterations, which may be attributed to fetal exposure to maternal tobacco smoking, alcohol consumption and several lifestyle factors in the first few years of life. This review aims to study the effects of teratogen exposure in utero on vascular dysfunction in offspring and consider mediators and pathways originating from the fetal environment. (2) Methods: Eligible studies were identified in the PubMed, Scopus and Web of Science databases. After the full-text screening, 20 articles were included in the narrative synthesis. (3) Results: The literature presents evidence supporting the detrimental effects of fetal exposure to tobacco smoking on vascular alterations in both human and animal studies. Alcohol exposure impaired endothelial dilation in animal studies, but human studies on both tobacco and alcohol exposure are still sparse. Reduction in nitric oxide (NO) bioavailability and alterations in the epigenome in infants through the upregulation of pro-oxidative and proinflammatory genes may be the common denominators. (4) Conclusion: While maternal smoking and alcohol consumption have more negative outcomes on the infant in the short term, several factors during the first few years of life may mediate the development of vascular dysfunction. Therefore, more prospective studies are needed to ascertain the long-term effects of teratogen exposure, specifically in South Africa.

1D-model of the human liver circulatory system

Background and objectiveBlood flow rate and pressure can be measured in vivo by invasive and non-invasive techniques in the large vessels of the hepatic vasculature, but it is not possible to do so along the entire liver circulatory system. Here, we develop a novel 1D model of the liver circulatory system to obtain the hemodynamic signals from macrocirculation to microcirculation with a very low computational cost. MethodsThe model considers structurally well-defined elements that constitute the entire hepatic circulatory system, the hemodynamics (the temporal-dependence of the blood flow rate and pressure), and the elasticity of the vessel walls. ResultsUsing flow rate signals from in vivo measurements as inputs in the model, we obtain pressure signals within their physiological range of values. Furthermore, the model allows to get and analyze the blood flow rate and pressure signals along any vessel of the hepatic vasculature. The impact of the elasticity of the different model components on the inlet pressures is also tested. ConclusionsA 1D model of the entire blood vascular system of the human liver is presented for the first time. The model allows to obtain the hemodynamic signals along the hepatic vasculature at a low computational cost. The amplitude and shape of the flow and pressure signals has hardly been studied in the small liver vessels. In this sense, the proposed model is a useful non-invasive exploration tool of the characteristics of the hemodynamic signals. In contrast to models that partially address the hepatic vasculature or those using an electrical analogy, the model presented here is made entirely of structurally well-defined elements. Future works will allow to directly emulate structural vascular alterations due to hepatic diseases and studying their impact on pressure and blood flow signals at key locations of the vasculature.

JS-HR-1: UPDATE OF VASCULAR FUNCTION

Atherosclerosis has two aspects: vascular dysfunction and vascular structural alterations. Both vascular dysfunction and vascular structural alterations are associated with future cardiovascular events. Therefore, the assessments of vascular function and vascular structural alterations may be useful not only for the assessment of the severity of atherosclerosis but also for the stratification of cardiovascular risk. Flow-mediated vasodilation and reactive hyperemia index as indices of endothelial function, nitroglycerine-induced vasodilation as an index of vascular smooth muscle function, and pulse wave velocity as an index of arterial stiffness, have been used for the assessment of vascular function in clinical settings. In this session, we summarize the updated information on the usefulness of vascular function tests in the management of patients with cardiovascular risk factors.

Super-Resolution Ultrasound Imaging Provides Quantification of the Renal Cortical and Medullary Vasculature in Obese Zucker Rats: A Pilot Study.

Obesity is a risk factor of chronic kidney disease (CKD), leading to alterations in the renal vascular structure. This study tested if renal vascular density and tortuosity was quantifiable in vivo in obese rats using microbubble-based super-resolution ultrasound imaging. The kidneys of two 11-week-old and two 20-week-old male obese Zucker rats were compared with age-matched male lean Zucker rats. The super-resolution ultrasound images were manually divided into inner medulla, outer medulla, and cortex, and each area was subdivided into arteries and veins. We quantified vascular density and tortuosity, number of detected microbubbles, and generated tracks. For comparison, we assessed glomerular filtration rate, albumin/creatinine ratio, and renal histology to evaluate CKD. The number of detected microbubbles and generated tracks varied between animals and significantly affected quantification of vessel density. In areas with a comparable number of tracks, density increased in the obese animals, concomitant with a decrease in glomerular filtration rate and an increase in albumin/creatinine ratio, but without any pathology in the histological staining. The results indicate that super-resolution ultrasound imaging can be used to quantify structural alterations in the renal vasculature. Techniques to generate more comparable number of microbubble tracks and confirmation of the findings in larger-scale studies are needed.

Resolvin D2 prevents cardiovascular damage in angiotensin II-induced hypertension

Introduction: Vascular functional and structural alterations induced by hypertension are greatly influenced by low- grade chronic inflammation. Resolution of inflammation is orchestrated by specialized lipid pro-resolving mediators (SPMs), which derive from n3 fatty acids (PUFAs). Previous evidence suggest that SPM prevent vascular damage in several pathological situations including atherosclerosis or vascular restenosis. Among SPMs, resolvins (Rv) seem to have beneficial effects in some cardiovascular pathologies, but little is known about their effect on cardiovascular damage in hypertension. Objective: The aim of this study was to evaluate the effects of resolvin D2 (RvD2) in blood pressure and cardiovascular damage associated with hypertension. Material and methods: aorta, mesenteric resistance arteries (MRA), heart and peritoneal macrophages were taken from C57BL/6J mice, infused or not with angiotensin II (AngII; 1,44mg/kg/day; for 14 days) in presence or absence of RvD2 (100ng/mice, every second day, started before AngII infusion). Blood pressure was measured by tail-cuff plethysmography. Cardiac and vascular function and structure were studied with wire and pressure myographs, confocal microscopy, histological staining, and echocardiography. Circulating leucocyte were analyzed by flow cytometry and macrophages behavior by electrophysiology. Gene expression was analyzed with RT-PCR. Results: Aorta or heart from AngII-infused mice showed altered expression of enzymes and receptors involved in SPMs biosynthesis and signaling. We also observed a downregulation of SPMs in heart tissues from these mice including 17R-RvD1 and RvE3. Treatment with RvD2 partially prevented the increase in blood pressure and in the content of circulating immune cells induced by AngII. RvD2 treatment also improved cardiac hypertrophy, fibrosis and dysfunction. Moreover, RvD2 treatment reduced vascular hypercontractility and endothelial dysfunction induced by AngII likely because of enhanced NO and PGI2 availability. RvD2 normalized AngII-induced vascular remodeling by decreasing media thickness and number of vascular smooth muscle cell, while it did not affect vascular stiffness. Finally, RvD2 reduced aortic and cardiac leukocyte infiltration and shifted macrophage phenotype towards a pro-resolving phenotype. Conclusion: Our data shows that RvD2 treatment limits the cardiovascular alterations induced by hypertension. These findings highlight that activating resolution mechanisms by treatment with RvD2 may represent a novel therapeutic strategy for the treatment of cardiovascular alterations associated to hypertension.

Deep Learning Approach to Nailfold Capillaroscopy Based Diabetes Mellitus Detection

Diabetes mellitus is a commonly occurring chronic metabolic disorder which has affected almost 400 million people around the world. It can lead to vascular structure alterations and various renal, cardiovascular, and neurologicalcomplications claiming several lives. Since diabetes mellitus results is vascular structure changes, NailfoldCapillaroscopy(NFC) based approach can be employed for the detection of diabetes. NFC is an inexpensive, non-invasive method which involves acquisition of images of capillaries in the nail bed region using a USB digital microscope. Qualitative parameters of the capillaries such as tortuosity, hemorrhages, angiogenesis, elongated capillariesand quantitative parameters like length, width and mean capillary density are considered for diabetes detection. About 600 capillary images of healthy and diabetic subjects were collected and further data augmentation was performed to increase this to 1018 images dataset. This paper focuses on using NFC to obtain capillary images and employdeep learning-based object detection algorithm to localize these capillary loops on the nailbed and differentiate them into five classes namely, normal, wide, elongated, tortuosity and hemorrhages. This classification is of prominent significance to medical practitioners as this helps in gauging the severity and progressionof the disorder.

Ultrafast Doppler imaging and ultrasound localization microscopy reveal the complexity of vascular rearrangement in chronic spinal lesion

Acute spinal cord injury (SCI) leads to severe damage to the microvascular network. The process of spontaneous repair is accompanied by formation of new blood vessels; their functionality, however, presumably very important for functional recovery, has never been clearly established, as most studies so far used fixed tissues. Here, combining ultrafast Doppler imaging and ultrasound localization microscopy (ULM) on the same animals, we proceeded at a detailed analysis of structural and functional vascular alterations associated with the establishment of chronic SCI, both at macroscopic and microscopic scales. Using a standardized animal model of SCI, our results demonstrate striking hemodynamic alterations in several subparts of the spinal cord: a reduced blood velocity in the lesion site, and an asymmetrical hypoperfusion caudal but not rostral to the lesion. In addition, the worsening of many evaluated parameters at later time points suggests that the neoformed vascular network is not yet fully operational, and reveals ULM as an efficient in vivo readout for spinal cord vascular alterations. Finally, we show statistical correlations between the diverse biomarkers of vascular dysfunction and SCI severity. The imaging modality developed here will allow evaluating recovery of vascular function over time in pre-clinical models of SCI. Also, used on SCI patients in combination with other quantitative markers of neural tissue damage, it may help classifying lesion severity and predict possible treatment outcomes in patients.

Combined Fluorescence and Optoacoustic Imaging for Monitoring Treatments against CT26 Tumors with Photoactivatable Liposomes.

Simple SummaryA new approach of combined optoacoustic (OA) and fluorescence (FL) imaging for in vivo real-time tracing photosensitizer (PS) kinetics and functional vascular effects in the treated area was developed. FL monitoring using a photoactivatable multi-inhibitor liposomal (PMILs) platform, demonstrates enhancement of PS accumulation in tumor, 24 h post-treatment. OA monitoring revealed the alterations of the tumor vasculature structure after treatment, which is in good agreement with the histological data that shows five times higher percentage of hemorrhages in PMIL treated mice compared to the untreated group.The newly developed multimodal imaging system combining raster-scan optoacoustic (OA) microscopy and fluorescence (FL) wide-field imaging was used for characterizing the tumor vascular structure with 38/50 μm axial/transverse resolution and assessment of photosensitizer fluorescence kinetics during treatment with novel theranostic agents. A multifunctional photoactivatable multi-inhibitor liposomal (PMILs) nano platform was engineered here, containing a clinically approved photosensitizer, Benzoporphyrin derivative (BPD) in the bilayer, and topoisomerase I inhibitor, Irinotecan (IRI) in its inner core, for a synergetic therapeutic impact. The optimized PMIL was anionic, with the hydrodynamic diameter of 131.6 ± 2.1 nm and polydispersity index (PDI) of 0.05 ± 0.01, and the zeta potential between −14.9 ± 1.04 to −16.9 ± 0.92 mV. In the in vivo studies on BALB/c mice with CT26 tumors were performed to evaluate PMILs’ therapeutic efficacy. PMILs demonstrated the best inhibitory effect of 97% on tumor growth compared to the treatment with BPD-PC containing liposomes (PALs), 81%, or IRI containing liposomes (L-[IRI]) alone, 50%. This confirms the release of IRI within the tumor cells upon PMILs triggering by NIR light, which is additionally illustrated by FL monitoring demonstrating enhancement of drug accumulation in tumor initiated by PDT in 24 h after the treatment. OA monitoring revealed the largest alterations of the tumor vascular structure in the PMILs treated mice as compared to BPD-PC or IRI treated mice. The results were further corroborated with histological data that also showed a 5-fold higher percentage of hemorrhages in PMIL treated mice compared to the control groups. Overall, these results suggest that multifunctional PMILs simultaneously delivering PDT and chemotherapy agents along with OA and FL multi-modal imaging offers an efficient and personalized image-guided platform to improve cancer treatment outcomes.

Vasoconstrictor antagonism improves functional and structural vascular alterations and liver damage in rats with early NAFLD

Background & AimsIntrahepatic vascular resistance is increased in early non-alcoholic fatty liver disease (NAFLD), potentially leading to tissue hypoxia and triggering disease progression. Hepatic vascular hyperreactivity to vasoconstrictors has been identified as an underlying mechanism. This study investigates vasoconstrictive agonism and antagonism in 2 models of early NAFLD and in non-alcoholic steatohepatitis (NASH).MethodsThe effects of endothelin-1 (ET-1), angiotensin II (ATII) and thromboxane A2 (TxA2) agonism and antagonism were studied by in situ ex vivo liver perfusion and preventive/therapeutic treatment experiments in a methionine-choline-deficient diet model of steatosis. Furthermore, important results were validated in Zucker fatty rats after 4 or 8 weeks of high-fat high-fructose diet feeding. In vivo systemic and portal pressures, ex vivo transhepatic pressure gradients (THPG) and transaminase levels were measured. Liver tissue was harvested for structural and mRNA analysis.ResultsThe THPG and consequent portal pressure were significantly increased in both models of steatosis and in NASH. ET-1, ATII and TxA2 increased the THPG even further. Bosentan (ET-1 receptor antagonist), valsartan (ATII receptor blocker) and celecoxib (COX-2 inhibitor) attenuated or even normalised the increased THPG in steatosis. Simultaneously, bosentan and valsartan treatment improved transaminase levels. Moreover, bosentan was able to mitigate the degree of steatosis and restored the disrupted microvascular structure. Finally, beneficial vascular effects of bosentan endured in NASH.ConclusionsAntagonism of vasoconstrictive mediators improves intrahepatic vascular function. Both ET-1 and ATII antagonists showed additional benefit and bosentan even mitigated steatosis and structural liver damage. In conclusion, vasoconstrictive antagonism is a potentially promising therapeutic option for the treatment of early NAFLD.Lay summaryIn non-alcoholic fatty liver disease (NAFLD), hepatic blood flow is impaired and the blood pressure in the liver blood vessels is increased as a result of an increased response of the liver vasculature to vasoconstrictors. Using drugs to block the constriction of the intrahepatic vasculature, the resistance of the liver blood vessels decreases and the increased portal pressure is reduced. Moreover, blocking the vasoconstrictive endothelin-1 pathway restored parenchymal architecture and reduced disease severity.

Metabolic syndrome is related to vascular structural alterations but not to functional one both in hypertensives and healthy subjects

Abstract Background Metabolic Syndrome (MS) has been related to an impairment in arterial structural and functional properties with heterogeneous results. Purpose In this study we focused on the effects of MS on arterial carotid-femoral Pulse Wave Velocity (PWV) and common carotid Intima Media Thickness (IMT) in two different populations, one of hypertensive patients and one of healthy controls. Methods We enrolled 816 consecutive hypertensive (HT) and 536 healthy controls. Vascular structural (IMT) and functional (PWV) properties were evaluated. NCEP-ATP-III criteria were used for diagnosis of MS. Results MS was diagnosed in 26.9% and 6.9% in hypertensive and control subjects, respectively. PWV was similar in controls with and without MS (7.7±1.9 vs 7.6±1.1 m/s, p=0.69), while IMT was higher in controls with than those without MS (0.64±0.18 vs 0.57±0.13 mm, p=0.02). Hypertensives with MS were older (57.9±12.2 vs 52.7±14.1 years, p<0.001) and showed higher PWV (9.0±2.3 vs 8.4±2.1 m/s, p=0.001) and IMT (0.72±0.22 vs 0.65±0.17 mm, p<0.001) than those without MS, however at the age-adjusted analysis only the difference in IMT was confirmed (p=0.007). Regression models showed that MS was an independent determinant of IMT in both controls (β=0.08, p=0.03) and hypertensives (β=0.08, p=0.01), but not of PWV either in controls (β=0.006, p=0.886 and β=0.04, p=0.19, respectively). Conclusions The main finding of our work is that MS is a significant determinant of IMT while this is not the case for PWV. This result has been confirmed both in hypertensive subjects and in healthy controls. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): ASST Grande Ospedale Metropolitano Niguarda

Intermittent hypoxia-related alterations in vascular structure and function: a systematic review and meta-analysis of rodent data.

Obstructive sleep apnoea and the related intermittent hypoxia (IH) are widely recognised as risk factors for incident cardiovascular diseases. Numerous studies support the deleterious vascular impact of IH in rodents but an overall interpretation is challenging owing to heterogeneity in rodent species investigated and the severity and duration of IH exposure. To clarify this major issue, we conducted a systematic review and meta-analysis to quantify the impact of IH on systemic artery structure and function depending on the different IH exposure designs. We searched PubMed, Embase and Web of Science, and included 125 articles in a meta-analysis, among them 112 using wild-type rodents and 13 using apolipoprotein E knockout (ApoE-/-) mice. We used the standardised mean difference (SMD) to compare results between studies. IH significantly increased mean arterial pressure (+13.90 (95% CI 11.88-15.92) mmHg), and systolic and diastolic blood pressure. Meta-regressions showed that mean arterial pressure change was associated with strain and year of publication. IH altered vasodilation in males but not in females and increased endothelin-1-induced but not phenylephrine-induced vasoconstriction. Intima-media thickness significantly increased upon IH exposure (SMD 1.10 (95% CI 0.58-1.62); absolute values +5.23 (2.81-7.84) µm). This increase was observed in mice but not in rats and was negatively associated with age. Finally, IH increased atherosclerotic plaque size in ApoE-/- mice (SMD 1.08 (95% CI 0.80-1.37)). Our meta-analysis established that IH, independently of other confounders, has a strong effect on vascular structure and physiology. Our findings support the interest of identifying and treating sleep apnoea in routine cardiology practice.

The Neurovascular Unit in Dementia: An Opinion on Current Research and Future Directions.

Dementia is a burgeoning public health crisis, with 50 million people currently affected worldwide (Prince et al., 2015). As the population ages, this figure is set to rise dramatically by 40% over the next 12 years (Prince et al., 2015). Dementia is an umbrella term for several disorders which result in the progressive loss of memory or other cognitive functions (Scott and Barrett, 2007). It remains an incurable disease, and current therapeutics have limited efficacy at slowing disease progression for one third of patients (Rockwood et al., 2008). Of the dementia sub-types, Alzheimer's disease (AD) remains the most prevalent, accounting for ~60–70% cases (Alzheimer's-Society, 2016). Vascular dementia (VaD) is the second most common form and is responsible for ~20% of cases, with a further 10% being a combination of these two diseases (Alzheimer's-Society, 2016). However, in practise these distinctions are somewhat arbitrary given the significant overlap in altered vascular structure and function in both of these major sub-types (Kalaria and Ballard, 1999). At least 30% of patients with AD have evidence of cerebrovascular disease on post-mortem examination, and almost all have evidence of cerebral amyloid angiopathy, microvascular degeneration, and white matter lesions (Kalaria and Ballard, 1999). Similarly, one-third of patients with VaD exhibit pathology consistent with AD (e.g., hippocampal or temporal lobe atrophy) (Kalaria and Ballard, 1999). Longitudinal studies have demonstrated that vascular risk factors (e.g., hypertension), significantly increase the risk of both AD and VaD (Rius-Perez et al., 2018). In genetically at-risk individuals positive for apolipoprotein E4 (APOE4), atherosclerosis can increase the risk of AD by three-fold (Hoffmann et al., 2010). This article provides an opinion on the current evidence on the role of the neurovascular unit in dementia, for further information, several recent reviews are available on this topic (Nelson et al., 2016; Kisler et al., 2017).

In Memoriam: professor Antonio Salvetti (1936-2021).

In Memoriam: professor Antonio Salvetti (1936-2021).

Clinical outcomes of hypertensive disorders in pregnancy in the offspring during perinatal period, childhood, and adolescence.

Hypertensive disorders during pregnancy (HDP) could have significant clinical impact not only on the mother's, but also on the offspring's health. The clinical impact of HDP may be evident early in the perinatal period or during childhood and adolescence. The cardiovascular system seems to be primarily affected with higher rates of congenital heart defects reported from cohort studies in the offspring of mothers with HDP. HDP are associated with alterations in cardiac and vascular structure and higher BP during childhood. HDP may also affect brain development and could result in increased prevalence of adverse cognitive outcomes and neuropsychiatric disorders in children and adolescents. The kidney, immune, endocrine, and gastrointestinal system abnormalities could also have their origin in exposure to HDP. The aim of this narrative review is to examine the clinical impact of HDP on the offspring with a focus on the perinatal period, childhood, and adolescence.

Matrix Metalloproteinases and Arterial Hypertension: Role of Oxidative Stress and Nitric Oxide in Vascular Functional and Structural Alterations.

Various pathophysiological mechanisms have been implicated in hypertension, but those resulting in vascular dysfunction and remodeling are critical and may help to identify critical pharmacological targets. This mini-review article focuses on central mechanisms contributing to the vascular dysfunction and remodeling of hypertension, increased oxidative stress and impaired nitric oxide (NO) bioavailability, which enhance vascular matrix metalloproteinase (MMP) activity. The relationship between NO, MMP and oxidative stress culminating in the vascular alterations of hypertension is examined. While the alterations of hypertension are not fully attributable to these pathophysiological mechanisms, there is strong evidence that such mechanisms play critical roles in increasing vascular MMP expression and activity, thus resulting in abnormal degradation of extracellular matrix components, receptors, peptides, and intracellular proteins involved in the regulation of vascular function and structure. Imbalanced vascular MMP activity promotes vasoconstriction and impairs vasodilation, stimulating vascular smooth muscle cells (VSMC) to switch from contractile to synthetic phenotypes, thus facilitating cell growth or migration, which is associated with the deposition of extracellular matrix components. Finally, the protective effects of MMP inhibitors, antioxidants and drugs that enhance vascular NO activity are briefly discussed. Newly emerging therapies that address these essential mechanisms may offer significant advantages to prevent vascular remodeling in hypertensive patients.