Vascular Mechanisms Research Articles

Cerebral perfusion and amyloidosis in the oldest‐old

AbstractBackgroundCerebrovascular contributions to cognitive aging and Alzheimer’s disease (AD) risk represent a growing field in aging research. Studies in the young‐old have demonstrated the critical role of vascular dysregulation (i.e., altered cerebral blood flow) in relation to cognitive decline prior to the appearance of amyloid/tau biomarkers. However, cerebral perfusion has not been well‐studied in the oldest‐old (ages 90 and over), a rapidly growing population that may provide unique insight into resilience and protective factors against dementia in later life. We characterized amyloid and cerebral perfusion profiles of cognitively normal (CN) and cognitively impaired without dementia (CIND) oldest‐old individuals.MethodParticipants were 97 dementia‐free older adults (70 CN and 27 CIND) from the 90+ Study who had available neuroimaging (T1‐MRI, ASL‐MRI, Florbetapir‐PET), demographic, and clinical data. We examined differences between CN and CIND in regional perfusion in areas associated with AD risk (medial temporal lobe, posterior cingulate, precuneus, frontal cortex, inferior parietal lobe) and in amyloid burden using linear regression models controlling for age, sex, education, APOE4 status, and vascular risk factors.ResultCN and CIND groups did not differ in the characteristics compared (Table 1). CIND participants had lower CBF in the posterior cingulate/precuneus than the CN group, but groups did not differ in posterior cingulate/precuneus amyloid SUVR (Figure 1). Additionally, CIND had lower CBF than CN in the inferior parietal lobe but higher CBF in the medial temporal lobe and orbitofrontal cortex (Figure 2).ConclusionCIND individuals had lower regional perfusion in the posterior cingulate/precuneus, but groups did not differ in amyloidosis, highlighting the relationship between cerebrovascular function and cognitive status in the oldest‐old independent of amyloidosis. Our findings complement previously reported posterior cingulate/precuneus hypoperfusion in younger‐old individuals with cognitive impairment and AD. Interestingly, we observed greater medial temporal/frontal perfusion in CIND than CN, similar to previous studies demonstrating initial hyperperfusion preceding hypoperfusion across the CN‐CIND‐Dementia spectrum. This may represent a compensatory vascular mechanism supporting cognition in individuals at greater risk of developing dementia. Future studies will further characterize this cohort with longitudinal perfusion analyses, neuropsychological correlates, and relationships between perfusion and other indices of cerebrovascular dysfunction.

Treatment of patients with erectile dysfunction by physiotherapy. Literature review

Erectile dysfunction is one of the most frequent sexual disorders in men and is found in 10-52% of men in the general population.
 The disease is polyetiological, involving psychogenic, vascular, neurological, urological, and endocrine mechanisms.
 The relevance of this problem lies in the high damage to the mental health of the patient, leading to a deterioration in his quality of life. In addition, drug therapy with the use of type 5 phosphodiesterase inhibitors is accompanied by headaches, skin flushing, heartburn, nasal congestion and dizziness, visual impairment, and muscle pain. In this regard, it became necessary to use physiotherapeutic methods of treatment to restore erectile function with minimal side effects.
 This review also presents pathogenetic substantiated basic physiotherapeutic methods for treating patients with erectile dysfunction using pelvic floor muscle training, aerobic sports exercises, transcutaneous electrical nerve stimulation, manual therapy and mechanical vibration therapy.

Subject-specific one-dimensional fluid dynamics model of chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) develops due to the accumulation of blood clots in the lung vasculature that obstructs flow and increases pressure. The mechanobiological factors that drive progression of CTEPH are not understood, in part because mechanical and hemodynamic changes in the small pulmonary arteries due to CTEPH are not easily measurable. Using previously published hemodynamic measurements and imaging from a large animal model of CTEPH, we applied a subject-specific one-dimensional (1D) computational fluid dynamic (CFD) approach to investigate the impact of CTEPH on pulmonary artery stiffening, time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) in extralobar (main, right, and left) pulmonary arteries and intralobar (distal to the extralobar) arteries. Our results demonstrate that CTEPH increases pulmonary artery wall stiffness and decreases TAWSS in extralobar and intralobar arteries. Moreover, CTEPH increases the percentage of the intralobar arterial network with both low TAWSS and high OSI, quantified by the novel parameter φ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\varphi$$\\end{document}, which is related to thrombogenicity. Our analysis reveals a strong positive correlation between increases in mean pulmonary artery pressure (mPAP) and φ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\varphi$$\\end{document} from baseline to CTEPH in individual subjects, which supports the suggestion that increased φ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\varphi$$\\end{document} drives disease severity. This subject-specific experimental–computational framework shows potential as a predictor of the impact of CTEPH on pulmonary arterial hemodynamics and pulmonary vascular mechanics. By leveraging advanced modeling techniques and calibrated model parameters, we predict spatial distributions of flow and pressure, from which we can compute potential physiomarkers of disease progression. Ultimately, this approach can lead to more spatially targeted interventions that address the needs of individual CTEPH patients.

Abstract 15509: “Root” Endothelial Cells: A Novel Population That Regulates Lung Capillary and Artery Maintenance and Repair

Introduction: Pulmonary capillary endothelial cells (ECs) are vital for various lung functions, such as maintaining the capillary network, promoting angiogenesis and facilitating gas and nutrient exchange. Recent advancements in single-cell transcriptomics have uncovered novel populations of general capillary ECs (gCaps) in the lungs. Understanding specialized EC types provides valuable insights into pulmonary vascular diseases. We aimed to challenge current understanding of the regenerative capabilities of lung resident ECs. Methods: Highly enriched ECs isolated from rat and mouse lungs underwent single-cell transcriptomics to explore EC population diversity. Results: UMAP annotation of ECs identified five novel general capillary cell populations (gCaps A-E). Lineage confirmation was achieved by Apelin receptor expression. Two distinct zonations (AV-zonation) were observed between pulmonary artery and vein ECs, with specific gCaps phenotypes (A: Clic4+, B: Flot1+, D: Scn7a+, E: Lingo2+), indicating a gradual phenotypic transition from arterial to vein ECs. Within the AV-zonation, a small population of gCapB (Flot1+) cells, resided at the interface of small artery ECs and gCap A and D, exhibiting characteristics of Root cells. RNA velocity analysis suggested Root cells as the origin of capillary and arterial cell lineages. PAGA analysis revealed high transcriptional similarity between gCapB and gCaps A, D, E and arterial cells, suggesting gCapB's role in capillary and arteriole formation and repair. Root cells exhibited upregulation of transcription factors Fos and Jun, promoting EC proliferation and angiogenesis, along with the Foxo and associated cell cycle regulation pathways. Root cells also displayed high G2M and S scores, indicating mitotic activity, supporting their role as the origin of capillary and arterial ECs. Elevated expression of CDKn1a and 1c, crucial for stem cell maintenance and differentiation further implied the repair potential of Root cells. Conclusions: Root Cells (gCapB) play a crucial role in regulating capillary and arteriole formation and repair by serving as a source of capillary and arterial ECs. These findings enhance our understanding of pulmonary vascular maintenance and repair mechanisms.

Abstract 11966: Translational Cardioinformatics: Neutrophil-Derived Translocator Protein as a Novel Regulator of Myocarditis and Coronary Artery Aneurysm in Kawasaki Disease and Multisystem Inflammatory Syndrome in Children

Introduction: Cardiovascular disease (CVD) in Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) lead to increased mortality through myocardial infarction. Hypothesis: Since KD and MIS-C are shaped by the same immune continuum, the cardiac pathologies and lethal complications may be averted by targeting a key regulator controlling both diseases; however, the pathogenic drivers are largely undefined. Methods: Through integrated, multi-cohort, single-cell meta-analysis of KD and MIS-C PBMC scRNA-seq profiles, we investigated the immunological drivers associated with systemic damage and cardiac pathologies, compared with other pediatric diseases, and validated across independent cohorts of KD, MIS-C, and myocardial infarction. Via cheminformatics approaches, we identified FDA-approved drugs for repurposing. Results: We found the expansion and hyperactivation of CD177 + neutrophils in KD and MIS-C, but not in other pediatric diseases. CD177 + neutrophils overexpressed markers and causal mediators of CVD development, supported by activation of prognostic CVD gene signatures (acute CVD, major adverse cardiovascular and limb events, and myocardial infarction). CD177 + neutrophils’ overactivated effector repertoire may mediate systemic inflammation and molecular damage via a vascular homing mechanism. We identified a dysfunctional SPI1-dependent regulatory network shared by KD and MIS-C during neutrophil hyperactivation, as well as key regulators which may induce cardiac disorders. Importantly, we found that TSPO is associated with myocarditis and coronary artery aneurysm, disease severity, IVIG treatment, and patient recovery. Via independent cohorts analyses, we validated TSPO as a prime target against KD and MIS-C pathologies. Murine myocardial infarction model confirmed the cardiac hyper-infiltration of hyperactivated CD177 + neutrophils. Lastly, we identified FDA-approved drugs against KD and MIS-C neutrophil hyperactivation. Conclusions: Collectively, CD177 + neutrophils have a pivotal role in KD/MIS-C systemic pathologies, clinical severity, and prognosis. We suggest drugs that can be developed as a single therapeutic strategy against either KD or MIS-C for clinical translation.

Abstract 12907: Aging Drives Cerebrovascular Network Remodeling and Functional Changes in the Mouse Brain

Introduction: Cerebrovascular dysfunction has been implicated in age-related cognitive decline and dementia, but the underlying vascular mechanisms are not well understood. An improved understanding of the nature of normal cerebrovascular aging is needed to help to establish the role that vascular dysfunction might play in cognitive decline and dementia. Methods: Here, we asked how normal aging differentially impacts the vascular structure and function in different brain areas in mice. We investigated structural changes in aged cerebrovascular networks and pericytes utilizing serial two-photon tomography (STPT). To further investigate potential remodeling of different vascular compartments and pericyte subtypes, we utilized tissue clearing, 3D immunolabeling, and light sheet fluorescence microscopy (LSFM) imaging. We also assessed how healthy aging impacts brain hemodynamics in response to voluntary locomotion and whisker stimulation in awake, head-fixed mice using wide field optical signal imaging and two-photon imaging. We tested mice of both sexes at 2-month, 18-month (early aging), and 24-month (late aging) of age. Results: Whole-brain vascular tracing using STPT showed an overall ~10% decrease in vascular length and branching density, and LSFM imaging with 3D immunolabeling further revealed increased arteriole tortuosity in aged brains. We also uncovered a selective vascular and pericyte loss in deep cortical layers, basal forebrain regions, and the hippocampal network. This may contribute to their regional vulnerabilities in neurodegenerative disorders. Moreover, our in vivo imaging in awake, head-fixed mice identified delayed neurovascular coupling response and inefficient oxygen delivery in aged brains. Conclusions: Our study reveals aging-related brain-wide changes in vascular and mural cell types that can explain vulnerability and resilience of different brain areas in normal aging. Moreover, we identified an age-related decrease in brain oxygenation and delayed neurovascular coupling responses which can be linked with cognitive impairment in aged brains. These aging-related changes will serve as a common factor to understand many neurodegenerative disorders and cognition decline in the elderly population.

Vascular tissue reconstruction by monocyte subpopulations on small-diameter acellular grafts via integrin activation

Although the clinical application of cell-free tissue-engineered vascular grafts (TEVGs) has been proposed, vascular tissue regeneration mechanisms have not been fully clarified. Here, we report that monocyte subpopulations reconstruct vascular-like tissues through integrin signaling. An Arg-Glu-Asp-Val peptide-modified acellular long-bypass graft was used as the TEVG, and tissue regeneration in the graft was evaluated using a cardiopulmonary pump system and porcine transplantation model. In 1 day, the luminal surface of the graft was covered with cells that expressed CD163, CD14, and CD16, which represented the monocyte subpopulation, and they exhibited proliferative and migratory abilities. RNA sequencing showed that captured cells had an immune-related phenotype similar to that of monocytes and strongly expressed cell adhesion-related genes. In vitro angiogenesis assay showed that tube formation of the captured cells occurred via integrin signal activation. After medium- and long-term graft transplantation, the captured cells infiltrated the tunica media layer and constructed vascular with a CD31/CD105-positive layer and an αSMA-positive structure after 3 months. This finding, including multiple early-time observations provides clear evidence that blood-circulating monocytes are directly involved in vascular remodeling.

Aging is associated with impaired triggering of TRPV3-mediated cutaneous vasodilation: a crucial process for local heat exposure.

Sensing temperature is vitally important to adapt our body to environmental changes. Local warm detection is required to initiate regulation of cutaneous blood flow, which is part of the peripheral thermoregulatory mechanisms, and thus avoid damage to surrounding tissues. The mechanisms mediating cutaneous vasodilation during local heat stress are impaired with aging. However, the impact of aging on the ability of the skin to detect subtle thermal changes is unknown. Among heat-activated cation channels, transient receptor potential vanilloid 3 (TRPV3) is a thermo-sensor predominantly expressed on keratinocytes and involved in local vascular thermoregulatory mechanisms of the skin in young mice. In the present study, using a murine in vivo model of local heat exposure of the skin, we showed that heat-induced vasodilation was reduced in old mice associated with reduced expression of TRPV3 channels. We also found a decrease in expression and activity of TRPV3 channel, as well as reduced TRPV3-dependent adenosine tri-phosphate release in human primary keratinocytes from old donors. This study shows that aging alters the epidermal TRPV3 channels, which might delay the detection of changes in skin temperature, thereby limiting the mechanisms triggered for local vascular thermoregulation in the old skin.

Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk.

Psychiatric and obstetric diseases are growing threats to public health and share high rates of co-morbidity. G protein-coupled receptor signaling (e.g., vasopressin, serotonin) may be a convergent psycho-obstetric risk mechanism. Regulator of G Protein Signaling 2 (RGS2) mutations increase risk for both the gestational disease preeclampsia and for depression. We previously found preeclampsia-like, anti-angiogenic obstetric phenotypes with reduced placental Rgs2 expressionin mice. Here,we extend this to test whether conserved cerebrovascular and serotonergic mechanisms are also associated with risk for neurobiological phenotypes in the Rgs2 KO mouse. Rgs2 KO exhibited anxiety-, depression-, and hedonic-like behaviors. Cortical vascular density and vessel length decreased in Rgs2 KO; cortical and white matter thickness and cell densities were unchanged. In Rgs2 KO, serotonergic gene expression was sex-specifically changed (e.g., cortical Htr2a, Maoa increased in females but all serotonin targets unchanged or decreased in males); redox-related expression increased in paraventricular nucleus and aorta; and angiogenic gene expression was changed in male but not female cortex. Whole-cell recordings from dorsal raphe serotonin neurons revealed altered 5-HT1A receptor-dependent inhibitory postsynaptic currents (5-HT1A-IPSCs) in female but not male KO neurons. Additionally, serotonin transporter blockade by the SSRI sertraline increased the amplitude and time-to-peak of 5-HT1A-IPSCs in KO neurons to a greater extent than in WT neurons in females only. These results demonstrate behavioral, cerebrovascular, and sertraline hypersensitivity phenotypes in Rgs2 KOs, some of which are sex-specific. Disruptions may be driven by vascular and cell stress mechanisms linking the shared pathogenesis of psychiatric and obstetric disease to reveal future targets.

Punicalagin attenuates myocardial oxidative damage, inflammation, and apoptosis in isoproterenol-induced myocardial infarction in rats: Biochemical, immunohistochemical, and in silico molecular docking studies

Myocardial infarction (MI) is a life-threatening ischemic disease and is one of the leading causes of morbidity and mortality worldwide. Punicalagin (PU), the major ellagitannin found in pomegranates, is characterized by multiple antioxidant activities. The aim of this study is to assess the protective effects of PU against isoproterenol (ISO)-induced acute myocardial damage and to investigate its underlying vascular mechanisms using rat model. MethodsRats were randomly divided into five groups and were treated orally (p.o.) with PU (25 and 50 mg/kg) for 14 days. ISO was administered subcutaneously (S.C.) (85 mg/kg) on the 15th and 16th days to induce Myocardial infarction. Cardiac markers, oxidative stress markers, and inflammatory cytokines levels were determined in the heart tissue. Immunohistochemistry analysis was performed to determine the protein expression pathways of inflammation, apoptosis and oxidative stress (Nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (HO-1) in all the groups. In silico study was carried out to evaluate the molecular interaction of PU with some molecular targets. ResultsOur results showed that ISO-induced cardiac tissue injury was evidenced by increased serum creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH), associated with several histopathological changes. ISO also induced an increase of MDA, PCO, NO, and 8-hydroxy-2-deoxyguanosine (8-OHdG), along with a decrease of antioxidant enzyme activities in the myocardial tissues. In addition, an increase of TNF-α, NF-κB, IL-6, IL-1β, iNOS, Nrf2 and (HO-1) was observed. Pre-treatment with PU reduced myocardial infract area, ameliorated histopathological alterations in myocardium, and decreased activities of myocardial injury marker enzymes in ISO-induced rats. In addition, PU remarkably restored ISO-induced elevation of lipid peroxidation and decrease of antioxidants, significantly reduced myocardial pro-inflammatory cytokines concentrations in this animal model. Molecular docking analysis of PU with protein targets showed potent interactions with negative binding energies.In conclusion, PU can protect the myocardium from oxidative injury, inflammatory response, and cell death induced by ISO by upregulating Nrf2/HO-1 signaling and antioxidants.

Pericyte loss leads to microvessel remodeling and nasal polyp formation

Background Chronic rhinosinusitis (CRS) may be caused by increased vascular permeability and inflammatory cell leakage in the subepithelial tissue. Aims/objectives The aim of this study is to clarify the role of pericytes in tissue edema, microvessel dysfunction and vascular remodeling mechanisms in patients of CRS with nasal polyps (CRSwNP). Material and methods A total of 63 tissue samples were collected, including 42 CRSwNP samples (22 eosinophilic CRSwNP (eCRSwNP) and 20 non-eosinophilic CRSwNP (non-eCRSwNP) samples) and 21 samples of CRS without nasal polyps (CRSsNP). The samples were stained by immunofluorescence to measure microvessel density (MVD) and microvessel pericyte coverage index (MPI). Results We found that the albumin expression in the eCRSwNP group was significantly increased (p < .05). The MPI was significantly decreased (p <.05). There was a significant negative correlation between the MPI and the plasma albumin level (r=-0.82, p < .05). The MPI was negatively correlated with eosinophilic count (r=-0.77, p < .05). In the eCRSwNP group, the expressions of IL-4, Ang-1 and Ang-2 were increased compared with those in the control group. Conclusions and significance Pericyte loss may induce microvessel dysfunction, affect the development of interstitial edema and eosinophilic exosmosis in eCRSwNP, and contribute to the formation and maintenance of nasal polyps.

Chronic Disorders of Cerebral Circulation: a Challenge for the Family Doctor

The article examines modern views on the pathogenesis and clinical manifestations of chronic cerebral ischemia (CCI) and the possibilities of their pharmacotherapy. From this point of view, the requirements for choosing the optimal pharmacological strategy for pathological changes in the brain during ischemia are analyzed. The main goals of the clinical application of the strategy of neuroprotection in general, and in particular the need for a simultaneous effect on the neuronal, neurotransmitter and vascular mechanisms of the development of cognitive and general brain symptoms are considered. The necessity of using membrane-protective, cholinergic and vasotropic type of action is well founded. In this regard, the risks of polypharmacy in such patients and the arguments in favor of prescribing combined drugs were analyzed. The advantages of the innovative domestic combination containing citicoline and ginkgo biloba extract are considered in detail. The mechanisms of action and clinical effects of these components are analyzed with an emphasis on the prospects of their use in general medical practice. Special attention is paid to the justification of new opportunities provided by the synergistic effect of citicoline and ginkgo biloba extract when they are used in the form of a combined dosage form in comparison with monotherapy with these agents. The data on the safety of the use of the specified combination, as well as the scheme of dosage and course regimens, are given. The combination of citicoline + ginkgo biloba extract opens up new opportunities for family doctors in the pharmacotherapy of early cerebral vascular insufficiency symptoms.

Protective effects of low-intensity pulsed ultrasound (LIPUS) against cerebral ischemic stroke in mice by promoting brain vascular remodeling via the inhibition of ROCK1/p-MLC2 signaling pathway.

Vascular remodeling is essential for patients with cerebral ischemic stroke (CIS). Our previous study proved that low-intensity pulsed ultrasound (LIPUS) could increase cortical hemodynamics. However, the effects and mechanisms of LIPUS on cerebral vascular remodeling after CIS are still unknown. In this study, we applied LIPUS to the mouse brain at 0.5h after distal middle cerebral artery occlusion (dMCAO) and subsequently daily for a stimulation time of 30min. Results showed that compared with the dMCAO group, LIPUS markedly increased cerebral blood flow (CBF), reduced brain swelling, and improved functional recovery at day 3 after CIS. LIPUS promoted leptomeningeal vasculature remodeling, enlarged vascular diameter, and increased the average vessel length and density at day 3 after CIS. Proteomic analysis highlighted that LIPUS mainly participated in the regulation of actin cytoskeleton pathway. Rho kinase 1 (ROCK1) was downregulated by LIPUS and participated in regulation of actin cytoskeleton. Subsequently, we verified that ROCK1 was mainly expressed in pericytes. Furthermore, we demonstrated that LIPUS inhibited ROCK1/p-MLC2 signaling pathway after CIS, which had positive effects on vascular remodeling and cerebral blood circulation. In conclusion, our preliminary study revealed the vascular remodeling effects and mechanism of LIPUS in CIS, provided evidence for potential clinical application of LIPUS.

Studies on the Effects of Hypercholesterolemia on Mouse Ophthalmic Artery Reactivity.

Atherogenic lipoproteins may impair vascular reactivity, leading to tissue damage in various organs, including the eye. This study aimed to investigate whether ophthalmic artery reactivity is affected in mice lacking the apolipoprotein E gene (ApoE-/-), a model for hypercholesterolemia and atherosclerosis. Twelve-month-old male ApoE-/- mice and age-matched wild-type controls were used to assess vascular reactivity using videomicroscopy. Moreover, the vascular mechanics, lipid content, levels of reactive oxygen species (ROS), and expression of pro-oxidant redox enzymes and the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) were determined in vascular tissue. Unlike the aorta, the ophthalmic artery of ApoE-/- mice developed no signs of endothelial dysfunction and no signs of excessive lipid deposition. Remarkably, the levels of ROS, nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1), NOX2, NOX4, and LOX-1 were increased in the aorta but not in the ophthalmic artery of ApoE-/- mice. Our findings suggest that ApoE-/- mice develop endothelial dysfunction in the aorta by increased oxidative stress via the involvement of LOX-1, NOX1, and NOX2, whereas NOX4 may participate in media remodeling. In contrast, the ophthalmic artery appears to be resistant to chronic apolipoprotein E deficiency. A lack of LOX-1 expression/overexpression in response to increased oxidized low-density lipoprotein levels may be a possible mechanism of action.

Restoring Angiotensin Type 2 Receptor Function Reverses PFOS-Induced Vascular Hyper-Reactivity and Hypertension in Pregnancy.

Perfluorooctane sulfonic acid (PFOS) exposure during pregnancy induces hypertension with decreased vasodilatory angiotensin type-2 receptor (AT2R) expression and impaired vascular reactivity and fetal weights. We hypothesized that AT2R activation restores the AT1R/AT2R balance and reverses gestational hypertension by improving vascular mechanisms. Pregnant Sprague-Dawley rats were exposed to PFOS through drinking water (50 μg/mL) from gestation day (GD) 4-20. Controls received drinking water with no detectable PFOS. Control and PFOS-exposed rats were treated with AT2R agonist Compound 21 (C21; 0.3 mg/kg/day, SC) from GD 15-20. In PFOS dams, blood pressure was higher, blood flow in the uterine artery was reduced, and C21 reversed these to control levels. C21 mitigated the heightened contraction response to Ang II and enhanced endothelium-dependent vasorelaxation in uterine arteries of PFOS dams. The observed vascular effects of C21 were correlated with reduced AT1R levels and increased AT2R and eNOS protein levels. C21 also increased plasma bradykinin production in PFOS dams and attenuated the fetoplacental growth restriction. These data suggest that C21 improves the PFOS-induced maternal vascular dysfunction and blood flow to the fetoplacental unit, providing preclinical evidence to support that AT2R activation may be an important target for preventing or treating PFOS-induced adverse maternal and fetal outcomes.

Study of vascular sclerosing agent based on the dual mechanism of vascular endothelial cell damage-plasmin system inhibition

Venous malformations are a vascular disorder. Currently, the use of chemical sclerosing agents is a common clinical approach for the treatment of venous malformations. However, the effectiveness of existing sclerosing agents is unsatisfactory and often accompanied by severe side effects. In this study, we have developed a novel cationic surfactant-based sclerosing agent (POL-TA) by conjugating the plasmin inhibitor tranexamic acid (TA) with a nonionic surfactant polidocanol (POL) through an ester bond. POL-TA induces endothelial cell damage, triggering the coagulation cascade and thrombus formation. Moreover, it releases TA in vivo, which inhibits plasmin activity and the activation of matrix metalloproteinase (MMPs), thereby stabilizing the fibrin network of the thrombus and promoting vascular fibrosis. We have established a cell model using venous malformation endothelial cells and assessed the cellular damage and underlying mechanisms of POL-TA. The inhibitory effects of POL-TA on the plasmin-MMPs system were evaluated using MMP-9 activity assay kit. Additionally, the mice tail vein model was employed to investigate the vascular sclerosing effects and mechanisms of POL-TA.

Age-associated increases in middle cerebral artery pulsatility differ between men and women.

Mechanisms underlying sex differences in brain aging remain unclear but may relate to changes in cerebral pulsatile blood flow. Sex differences in the stiffening of the large arteries and expansion of pulse pressure with age may accelerate changes in pulsatile (i.e., discontinuous) blood flow in the brain that contribute to brain health. The purpose of this cross-sectional, secondary analysis was to examine sex differences in age-associated changes in large artery (aorta and carotid) stiffness, carotid pulse pressure, and cerebral pulsatility in 206 men and 217 women between 18 and 72 yr of age. Outcomes included aortic stiffness [carotid-femoral pulse wave velocity (cfPWV)] and carotid pulse pressure via tonometry, carotid β-stiffness via ultrasound, and middle cerebral artery (MCA) pulsatility index via transcranial Doppler. Regression analyses revealed a significant age-by-sex interaction, with women exhibiting a slower rate of change compared with men for cfPWV (β = -0.21, P = 0.04), and greater rate of change for carotid stiffness (β = 0.27, P = 0.02), carotid pulse pressure (β = 0.98, P < 0.001), and MCA pulsatility index (β = 0.49, P = 0.002) after adjustment for covariates. The significant age-by-sex interaction for MCA pulsatility was abolished after further adjustment for carotid pulse pressure. Women exhibit accelerated increases in cerebral pulsatility during midlife, likely driven by exaggerated increases in carotid stiffness and pulse pressure compared with men. These data suggest that there are disproportionate increases in cerebral pulsatility in women during midlife that could contribute to accelerated brain aging compared with men.NEW & NOTEWORTHY We identify sex-specific associations between increasing age and cerebral pulsatility and its vascular mechanisms. When compared with men, women in our cross-sectional analysis exhibited greater age-associated increases in carotid stiffness, carotid pulse pressure, and cerebral pulsatility particularly during midlife. These data suggest that the rapid expansion of pulse pressure during midlife contributes to an exaggerated increase in cerebral pulsatility among women and suggest a potential mechanism contributing to sex differences in brain aging.

Recent insights into mechanisms of hypoxia-induced vasodilatation in the human brain.

The cerebral vasculature manages oxygen delivery by adjusting arterial blood in-flow in the face of reductions in oxygen availability. Hypoxic cerebral vasodilatation, and the associated hypoxic cerebral blood flow reactivity, involve many vascular, erythrocytic and cerebral tissue mechanisms that mediate elevations in cerebral blood flow via micro- and macrovascular dilatation. This contemporary review focuses on in vivo human work - with reference to seminal preclinical work where necessary - on hypoxic cerebrovascular reactivity, particularly where recent advancements have been made. We provide updates with the following information: in humans, hypoxic cerebral vasodilatation is partially mediated via a - likely non-obligatory - combination of: (1) nitric oxide synthases, (2) deoxygenation-coupled S-nitrosothiols, (3) potassium channel-related vascular smooth muscle hyperpolarization, and (4) prostaglandin mechanisms with some contribution from an interrelationship with reactive oxygen species. And finally, we discuss the fact that, due to the engagement of deoxyhaemoglobin-related mechanisms, reductions in O2 content via haemoglobin per se seem to account for ∼50% of that seen with hypoxic cerebral vasodilatation during hypoxaemia. We further highlight the issue that methodological impediments challenge the complete elucidation of hypoxic cerebral reactivity mechanisms in vivo in healthy humans. Future research is needed to confirm recent advancements and to reconcile human and animal findings. Further investigations are also required to extend these findings to address questions of sex-, heredity-, age-, and disease-related differences. The final step is to then ultimately translate understanding of these mechanisms into actionable, targetable pathways for the prevention and treatment of cerebral vascular dysfunction and cerebral hypoxic brain injury.

Effects of chronic caffeine on patterns of brain blood flow and behavior throughout the sleep-wake cycle in freely behaving mice.

Caffeine has significant effects on neurovascular activity and behavior throughout the sleep-wake cycle. We used a minimally invasive microchip/video system to continuously record effects of caffeine in the drinking water of freely behaving mice. Chronic caffeine shifted both rest and active phases by up to 2 h relative to the light-dark cycle in a dose-dependent fashion. There was a particular delay in the onset of rapid eye movement (REM) sleep as compared with non-REM sleep during the rest phase. Chronic caffeine increased wakefulness during the active phase and consolidated sleep during the rest phase; overall, there was no net change in the amount of time spent in the wake, sleep, or REM sleep states during caffeine administration. Despite these effects on wakefulness and sleep, chronic caffeine decreased mean cerebral blood volume (CBV) during the active phase and increased mean CBV during the rest phase. Chronic caffeine also increased heart rate variability in both the sleep and wake states. These results provide new insight into the effects of caffeine on the biology of the sleep-wake cycle. Increased blood flow during sleep caused by chronic caffeine may have implications for its potential neuroprotective effects through vascular mechanisms of brain waste clearance.

Abstract P398: Reduced Expression Of Nfatc1 Protects Against Salt-sensitive Hypertension In Mice

Background: While nuclear factor of activated T cells-cytoplasmic 1 (NFATc1) is a transcription factor that canonically plays a role in the immune response, it is also widely expressed in non-immune cells. A recent trans-ethnic meta-analysis of genome-wide association studies (GWAS) found that the NFATC1 gene in humans was associated with chronic kidney disease. Additionally, renal Nfact1 mRNA expression was decreased during high-salt exposure in a salt-sensitive murine model, suggesting a link between NFATc1 and salt-sensitive hypertension. Methods: Here, young adult heterozygous Nfatc1 knockout mice (Het) and wild-type (WT) male mice on a salt-sensitive 129S6 background were studied. Systolic blood pressure (SBP) measurements were obtained by either tail cuff manometry with at least 2 weeks of training or implanted radiotelemetry with at least 2 weeks of recovery following surgery. SBP was recorded on standard chow (NSD), on a matched high-salt diet (HSD, 6% total NaCl), or on standard chow with 1000 ng/kg/min angiotensin II (AngII) delivered by osmotic minipump. Pressure natriuresis was examined by correlating 24 h SBP from telemetry with 24 h urine sodium collected in metabolic cages before and for 3 days after switching from NSD to HSD. Results: On NSD, there was no difference in SBP between WT and Het mice (127.8±9.9 vs 125.8±8.7 mmHg, n = 9/group). However, while WT mice displayed an expected elevation in SBP after 3 weeks on HSD, Het mice showed no change in SBP, resulting in a statistically significant difference between genotypes (143.4±8.9 vs 125.7±10.6 mmHg, p = 0.0024, n = 9/group). Pressure natriuresis curves were not significantly different between genotypes. SBP was not significantly different on AngII (167.6±22.2 vs 161.8±10.9 mmHg, n = 2/3). Conclusion: Our preliminary data shows that decreased Nfatc1 expression protects against salt-sensitive hypertension. However, this effect is not mediated through a change in pressure natriuresis, suggesting possible involvement of a vascular mechanism. NFATc1 is a potential therapeutic target in salt-sensitive hypertension.