Changes In Vascular Reactivity Research Articles

Abstract 59: Beclin-1-Dependent Autophagy Prevents Hyperaldosternism-Induced Endothelial Dysfunction And Hypertension

Hyperaldosteronism (HA), characterized by the overproduction of aldosterone (Aldo), leads to cardiovascular damage, including endothelial dysfunction. Beclin-1 (Becn1) is a key protein regulating autophagy, a recycling process for unwanted components. Whether HA disturbs autophagic flux in endothelial cells via Becn1 is unknown. We hypothesize that Becn1-dependent autophagic flux will improve endothelial function and inhibit the hypertension (HTN) in HA. 10-to-12-week-old male C57BL/6J (WT) or Becn1 knock-in mice (Becn1 Tg ) were infused with aldosterone for 14 days (600 µg/kg/day). Vascular function was studied in mesenteric arteries (MA) and blood pressure was analyzed by radiotelemetry. HA disrupted MA autophagic flux characterized by accumulation of LC3A/B and p62 and reduction in Becn1 expression and activity followed by suppressed acetylcholine (ACh)-induced vasodilation (% relaxation) in WT [WT: 91.5±1.1 vs HA: 56.7±2.7], whereas Becn1 Tg mice were protected from HA-induced HTN [mean blood pressure (mmHg) – WT_Aldo: 149.1±1.2 vs BCN1_Aldo: 118.1±0.8] and endothelial dysfunction [HA_Becn1 Tg : 92.8±2.9]. Given the link between the immune system and cardiovascular diseases, we investigated whether HA reduces autophagic flux and BCN1 in immune cells. HA led to the accumulation of LC3A/B and p62, and decreased BCN1 activity in peritoneal cavity cells of WT mice, however bone marrow transplant from Becn1 Tg mice into WT mice did not confer protection against HA-induced changes in vascular reactivity [WT to WT_HA: 51.2±1.3 vs Becn1 Tg to WT_HA: 53.8±1.9]. As a pharmacological approach, we accelerated autophagic flux by treating mice with spermidine (3 mM for 7 days), which subsequently improved endothelial function in HA [HA: 52.7±3.9 vs HA+spermidine: 88.9±3.9]. To assess the direct impact of Aldo on disrupting autophagy flux in endothelial cells, we treated mesenteric endothelial cells (MEC) with Aldo (0.1 µM for 24 hours). This treatment resulted in the accumulation of LC3A/B and p62 proteins and a reduction in BCN1 activity, accompanied by an upregulation in the mRNA expression of pro-inflammatory cytokines. All these effects were prevented by spermidine (100 uM for 3h). These findings reveal a novel pathway in HA-associated endothelial dysfunction and HTN, where Aldo disrupts autophagic flux and inflammation by suppressing BCN1 activity, positioning BCN1 as a pharmacological target for cardiovascular outcomes in HA.

Changes in cerebral vascular reactivity following mild repetitive head injury in awake rats: modeling the human experience.

The changes in brain function in response to mild head injury are usually subtle and go undetected. Physiological biomarkers would aid in the early diagnosis of mild head injury. In this study we used hypercapnia to follow changes in cerebral vascular reactivity after repetitive mild head injury. We hypothesized head injury would reduce vascular reactivity. Rats were maintained on a reverse light-dark cycle and head impacted daily at 24h intervals over three days. All head impacts were delivered while rats were fully awake under red light illumination. There was no neuroradiological evidence of brain damage. After the 3rd impact rats were exposed to 5% CO2 and imaged for changes in BOLD signal. All imaging was done while rats were awake without the confound of anesthesia. The data were registered to a 3D MRI rat atlas with 171 segmented brain areas providing site specific information on vascular reactivity. The changes in vascular reactivity were not uniform across the brain. The prefrontal cortex, somatosensory cortex and basal ganglia showed the hypothesized decrease in vascular reactivity while the cerebellum, thalamus, brainstem, and olfactory system showed an increase in BOLD signal to hypercapnia.

Perivascular Adipose Tissue and Uterine Artery Adaptations to Pregnancy.

Pregnancy is characterized by longitudinal maternal, physiological adaptations to support the development of a fetus. One of the cardinal maternal adaptations during a healthy pregnancy is a progressive increase in uterine artery blood flow. This facilitates sufficient blood supply for the development of the placenta and the growing fetus. Regional hemodynamic changes in the uterine circulation, such as a vast reduction in uterine artery resistance, are mainly facilitated by changes in uterine artery reactivity and myogenic tone along with remodeling of the uterine arteries. These regional changes in vascular reactivity have been attributed to pregnancy-induced adaptations of cell-to-cell communication mechanisms, with an emphasis on the interaction between endothelial and vascular smooth muscle cells. Perivascular adipose tissue (PVAT) is considered the fourth layer of the vascular wall and contributes to the regulation of vascular reactivity in most vascular beds and most species. This review focuses on mechanisms of uterine artery reactivity and the role of PVAT in pregnancy-induced maternal vascular adaptations, with an emphasis on the uterine circulation.

Characterization of Vascular Niche in Systemic Sclerosis by Spatial Proteomics.

Systemic sclerosis (SSc) is a connective tissue disease that can serve as a model to study vascular changes in response to inflammation, autoimmunity, and fibrotic remodeling. Although microvascular changes are the earliest histopathologic manifestation of SSc, the vascular pathophysiology remains poorly understood. We applied spatial proteomic approaches to deconvolute the heterogeneity of vascular cells at the single-cell level in situ and characterize cellular alterations of the vascular niches of patients with SSc. Skin biopsies of patients with SSc and control individuals were analyzed by imaging mass cytometry, yielding a total of 90 755 cells including 2987 endothelial cells and 4096 immune cells. We identified 7 different subpopulations of blood vascular endothelial cells (VECs), 2 subpopulations of lymphatic endothelial cells, and 3 subpopulations of pericytes. A novel population of CD34+;αSMA+ (α-smooth muscle actin);CD31+ VECs was more common in SSc, whereas endothelial precursor cells were decreased. Co-detection by indexing and tyramide signal amplification confirmed these findings. The microenvironment of CD34+;αSMA+;CD31+ VECs was enriched for immune cells and myofibroblasts, and CD34+;αSMA+;CD31+ VECs expressed markers of endothelial-to-mesenchymal transition. The density of CD34+;αSMA+;CD31+ VECs was associated with clinical progression of fibrosis in SSc. Using spatial proteomics, we unraveled the heterogeneity of vascular cells in control individuals and patients with SSc. We identified CD34+;αSMA+;CD31+ VECs as a novel endothelial cell population that is increased in patients with SSc, expresses markers for endothelial-to-mesenchymal transition, and is located in close proximity to immune cells and myofibroblasts. CD34+;αSMA+;CD31+ VEC counts were associated with clinical outcomes of progressive fibrotic remodeling, thus providing a novel cellular correlate for the crosstalk of vasculopathy and fibrosis.

Retinal Vascular Changes in Response to Hypoxia: A High-Altitude Expedition Study.

Westwood, Jessica, India Mayhook-Walker, Ciaran Simpkins, Andrew Darby-Smith, Dan Morris, and Eduardo Normando. Retinal vascular changes in response to hypoxia: a high-altitude expedition study. High Alt Med Biol. 25:49-59, 2024. Background: Increased tortuosity and engorgement of retinal vasculature are recognized physiological responses to hypoxia. This can lead to high-altitude retinopathy (HAR), but incidence reports are highly variable, and our understanding of the etiological mechanisms remains incomplete. This study quantitatively evaluated retinal vascular changes during an expedition to 4,167 m. Methods: Ten healthy participants summited Mount Toubkal, Morocco. Fundus images were taken predeparture, daily throughout the expedition, and 1 month postreturn. Diameter and tortuosity of four vessels were assessed, in addition to vessel density and features of HAR. Results: Significant (p ≤ 0.05) increases in tortuosity and diameter were observed in several vessels on high-altitude exposure days. There was a strong correlation between altitude and supratemporal retinal artery diameter on days 2, 3, and 6 of the expedition (r = 0.7707, 0.7951, 0.7401, respectively; p < 0.05). There was a significant increase in median vessel density from 6.7% at baseline to 10.0% on summit day. Notably there were no incidences of HAR. Conclusion: Physiological but not pathological changes were seen in this cohort, which gives insight into the state of the cerebral vasculature throughout this expedition. These results are likely attributable to relatively low altitude exposure, a conservative ascent profile, and the cohort's demographic. Future study must include daily retinal images at higher altitudes and take steps to mitigate environmental confounders. This study is relevant to altitude tourists, patients with diabetic retinopathy or retinal vein occlusion, and critically ill patients.

NTPDase1/CD39 Ectonucleotidase Is Necessary for Normal Arterial Diameter Adaptation to Flow.

NTPDase1/CD39, the major vascular ectonucleotidase, exerts thrombo-immunoregulatory function by controlling endothelial P2 receptor activation. Despite the well-described release of ATP from endothelial cells, few data are available regarding the potential role of CD39 as a regulator of arterial diameter. We thus investigated the contribution of CD39 in short-term diameter adaptation and long-term arterial remodeling in response to flow using Entpd1-/- male mice. Compared to wild-type littermates, endothelial-dependent relaxation was modified in Entpd1-/- mice. Specifically, the vasorelaxation in response to ATP was potentiated in both conductance (aorta) and small resistance (mesenteric and coronary) arteries. By contrast, the relaxing responses to acetylcholine were supra-normalized in thoracic aortas while decreased in resistance arteries from Entpd1-/- mice. Acute flow-mediated dilation, measured via pressure myography, was dramatically diminished and outward remodeling induced by in vivo chronic increased shear stress was altered in the mesenteric resistance arteries isolated from Entpd1-/- mice compared to wild-types. Finally, changes in vascular reactivity in Entpd1-/- mice were also evidenced by a decrease in the coronary output measured in isolated perfused hearts compared to the wild-type mice. Our results highlight a key regulatory role for purinergic signaling and CD39 in endothelium-dependent short- and long-term arterial diameter adaptation to increased flow.

Ultrasound-stimulated microbubbles enhanced vascular disruption in fractionated radiotherapy-treated tumours via ASMase activation.

Recent studies have indicated that radiotherapy affects tumour vasculature as well as tumour cells. The use of ultrasound-stimulated microbubbles (USMB) can potentially enhance the effects of radiotherapy through the activation of the acid sphingomyelinase [ASMase or sphingomyelin phosphodiesterase 1 (SMPD1)]-ceramide pathway. ASMase knockout (ASMase-/-) and wild-type (WT) mice bearing fibrosarcoma (MCA/129 tumour line) were treated with 10 Gy or 20 Gy in five fractions alongside or independently of USMB treatments. The results indicated that tumour responses to fractionated radiotherapy (fXRT) were enhanced when fXRT was coupled with USMB as part of the treatment regimen. Sphingosine-1-phosphate (S1P)-treated mice and ASMase-/- mice demonstrated radioresistance against fXRT alone, whereas only ASMase-/- mice showed radioresistance against fXRT treatment alone and when combined with USMB. Results indicated that in WT and S1P-treated cohorts, the use of USMB with fXRT enhanced the tumour response compared to use of USMB or fXRT alone. Although in WT and S1P-treated cohorts, there was enhanced vascular disruption, ASMase-/- cohorts demonstrated no significant vascular disruption, indicating the importance of ASMase in facilitating vascular changes in response to fXRT and USMB treatment.

Vascular adaptation to cancer beyond angiogenesis: The role of PTEN.

Cancer is a public health problem, and it needs blood vessels to grow. Knowing more about the processes of vascular adaptation to cancer improves our chances of attacking it, since the tumor for its extension needs such adaptation to satisfy its progressive demand for nutrients. The main objective of this review is to present the reader with some fundamental molecular pathways for vascular adaptation to cancer, highlighting within them the regulatory role of homologous tensin and phosphatase protein (PTEN). Hence the review describes vascular adaptation to cancer through somewhat known processes, such as angiogenesis, but emphasizes others that are much less explored, namely the changes in vascular reactivity and remodeling of the vascular wall -intima-media thickness and adjustments in the extracellular matrix- The role of PTEN in physiological and pathological vascular mechanisms in different types of cancer is deepened, as a crucial mediator in vascular adaptation to cancer, and points pending further exploration in cancer vascularization are suggested.

DEPENDENCE ON ANESTHESIOLOGY SUPPORT IN VICTIMS WITH COMBINED MINE-EXPLOSIVE THORACO-ABDOMINAL INJURIES AND PENETRATING HEAD INJURIES AT THE STAGE OF PREPARATION AND CONDUCTING OF AEROMEDICAL EVACUATION

Introduction. Explosive explosive injuries account for more than 50% of all injuries received in military battles, and the proportion of casualties among the civilian population is also increasing [1]. However, only limited research has been conducted on the pathophysiology of blast-induced brain injury, and the effect of changes in cerebral blood flow (CBF) or cerebral vascular reactivity on blast-induced brain injury has not been investigated [2]. Although secondary hypotension and hypoxemia are associated with increased mortality and morbidity after blunt head injury, the effect of secondary injury factors in blast injury is unknown [2]. TBI itself causes cerebral hypoperfusion, reduced oxygen delivery to the brain, excitotoxicity, and disruption of cerebral blood flow autoregulation, which explains the vulnerability of the affected brain to hypoxia and hypotension caused by blood loss [2,3].

Abstract 63: Age-related Changes In Gray Matter Cerebral Metabolism And Vascular Reactivity In Children

Introduction: Metabolic demand changes throughout childhood as the brain develops, peaking in the 2 nd decade of life. Cerebral blood flow (CBF) is dynamic throughout childhood, likely in response to the increased metabolic demand of brain development. Cerebrovascular reactivity (CVR) reflects the ability to further increase CBF in response to a stimulus, such as carbon dioxide (CO 2 ). We hypothesized that gray matter oxygen metabolism (GM CMRO 2 ) is increased in younger children, corresponding to higher GM CBF and lower GM CVR. Methods: CVR was calculated as the proportional change of a subject’s MRI-measured blood oxygen level dependent signal in response to an increase in end-tidal CO 2 administered by the RespirAct® RA-MR™ device. GM CMRO 2 was calculated voxel-by-voxel as the product of GM CBF (arterial spin labeling), GM oxygen extraction fraction (asymmetric spin echo), and arterial oxygen content (= Hb х (oxygen saturation)х1.34). Univariate relationships were tested using Spearman’s correlation coefficient, and corrected for multiple comparisons. Results: GM CVR, CBF, and CMRO 2 were calculated for 15 healthy participants (ages 8-19, 7 male). GM CMRO 2 was highest in young children and decreased with age (ρ=-0.68, P=0.005), as did CBF (ρ =-0.67, P=0.006). CVR was lower in young children, increasing with age (ρ=0.58, P=0.02). However, while GM CVR correlated with CBF (ρ=-0.64, P=0.01) it did not significantly associate with CMRO 2 (ρ=-0.43, P=0.114). Conclusion: Although GM CMRO 2 and CVR both have age-related changes, CVR does not directly correlate with CMRO 2 . Rather, their relationship may be moderated through other influences on CBF, as further study will investigate. Figure: Linear fits and 95% confidence intervals of subject data, including age, GM CBF, and GM CMRO 2 , versus GM CVR. P-values are from Spearman’s test for monotonic correlation.

Reduction of vascular reactivity in rat aortas following pilocarpine-induced status epilepticus

ObjectiveThe authors investigated changes in vascular reactivity in rats following pilocarpine-induced status epilepticus. MethodMale Wistar rats weighing between 250g and 300g were used. Status epilepticus was induced using 385 mg/kg i.p. pilocarpine. After 40 days the thoracic aorta was dissected and divided into 4 mm rings and the vascular smooth muscle reactivity to phenylephrine was evaluated. ResultsEpilepsy decreased the contractile responses of the aortic rings to phenylephrine (0.1 nM–300 mM). To investigate if this reduction was induced by increasing NO production with/or hydrogen peroxide L-NAME and Catalase were used. L-NAME (N-nitro-L arginine methyl ester) increased vascular reactivity but the contractile response to phenylephrine increased in the epileptic group. Catalase administration decreased the contractile responses only in the rings of rats with epilepsy. ConclusionsOur findings demonstrated for the first time that epilepsy is capable of causing a reduction of vascular reactivity in rat aortas. These results suggest that vascular reactivity reduction is associated with increased production of Nitric Oxide (NO) as an organic attempt to avoid hypertension produced by excessive sympathetic activation.

Cardioprotective Effects of Solidago microglossa DC. in Nicotine-Treated Hypertensive Rats.

Solidago microglossa DC. (Asteraceae), "arnica brasileira," is a Brazilian species popularly used to treat hypertension or renal ailments. This study investigated the cardioprotective effects of standardized S. microglossa extract (EESM) in nicotine-treated spontaneously hypertensive rats (SHRs). Moreover, the molecular mechanisms involved in the cardiovascular effects were also investigated. The acute toxicity was evaluated in female Wistar rats. Afterwards, six-month-old male spontaneously hypertensive rats received the EESM (14, 28, and 56 mg/kg), hydrochlorothiazide (25 mg/kg), and vehicle (filtered water; 0.1 mL/100 g) once daily for 28 days. All treatments were associated with 1.8 mg/kg of nicotine. At the end of the experimental period, the renal function, electrocardiographic profile, blood pressure, ventricular function, biochemical parameter, and mesenteric vascular bed reactivity were evaluated. Relative organ weights and cardiac morphometry were also investigated. Nicotine treatment in 6-month-old SHRs induced a significant reduction in renal function, with reduced urinary volume and lower renal elimination of sodium and creatinine. In addition, serum markers of the redox state and blood pressure levels remained significantly elevated, contributing to changes in vascular reactivity and left ventricular hypertrophy associated with reduced ventricular function. After 28 days of treatment, we found that the highest dose of EESM could mitigate all renal and cardiovascular changes developed by the nicotine-treated hypertensive rats. This study presented EESM as a possible cardioprotective drug that prevents cardiovascular dysfunctions in nicotine-treated hypertensive rats. Our data suggest EESM as a potential adjuvant therapy when cardioprotective effects are required.

The glycocalyx and calcium dynamics in endothelial cells.

The endothelial glycocalyx is a dynamic surface layer composed of proteoglycans, glycoproteins, and glycosaminoglycans with a key role in maintaining endothelial cell homeostasis. Its functions include the regulation of endothelial barrier permeability and stability, the transduction of mechanical forces from the vascular lumen to the vessel walls, serving as a binding site to multiple growth factors and vasoactive agents, and mediating the binding of platelets and the migration of leukocytes during an inflammatory response. Many of these processes are associated with changes in intracellular calcium levels that may occur through mechanisms that alter calcium entry in the endothelium or the release of calcium from the endoplasmic reticulum. Whether the endothelial glycocalyx can regulate calcium dynamics in endothelial cells is unresolved. Interestingly, during cardiovascular disease progression, changes in calcium dynamics are observed in association with the degradation of the glycocalyx and with changes in barrier permeability and vascular reactivity. Herein, we aim to provide a summarized overview of what is known regarding the role of the glycocalyx as a regulator of endothelial barrier and vascular reactivity during homeostatic and pathological conditions and to provide a perspective on how such processes may relate to calcium dynamics in endothelial cells, exploring a possible connection between components of the glycocalyx and calcium-sensitive pathways in the endothelium.

VESTIBULAR DYSFUNCTIONS IN CHRONIC BRAIN ISCHEMIA IN THE POST COVID PERIOD.

The aim: The aim of the study is the clinical-pathogenetic reasoning of vestibular dysfunctions (VD) development against the background of chronic brain ischemia in the presence of degenerative changes in the cervical spine (CS) in the post COVID period. Materials and methods: 82 patients, in the conditions of the clinical base of the Odessa National Medical University in 2019-2021 were examined. Group I with VD against the background of chronic brain ischemia (CBI) at the compensated phase; Group II with VD against the background of CBI at the subcom¬pensated phase (33 men; 49 women), aged from 18 to 55 years. The control group (CG) consisted of 20 patients of the corresponding gender and age. The condition of the state of the autonomic nervous system, vestibular functions, cervical spine, cerebral arteries and emotional condition were examined. Results: Vestibulo-ataxic disorders were higher compared to CG and increased along with the degree of brain damage. An important aspect of the development of VD is autonomic dysfunction against the background of pathological autonomic characteristics with predominant parasympathetic orientation of autonomic tone, especially in the case of insufficiency of autonomic recativity (AR) and pathological autonomic support of activity. Such changes significantly increased in the presence of subcompensation of CBI. The correlation between psychoemotional disorders and changes in autonomic characteristics with VD against the background of CBI with initial regularities depending on the degree of brain damage was defined. The progression of CBI is facilitated by coronavirus infection and manifested in autonomic and psychoemotional dysfunctions. A characteristic hemodynamic feature in groups with compensated and subcompensated CBI is the presence of reduced perfusion in basilar (BA) and vertebral (VA) arteries. Changes in cerebral vascular reactivity with a decrease in cerebrovascular reactivity indicators were characteristic of the subcompensated phase of CBI. Hyperactivity to rotational functional loads in both clinical groups has a high correlation with the presence of stair descent and, to a lesser extent, isolated instability in CS. Conclusions: 1. The occurrence of VD is facilitated by the presence of autonomic dysfunction and degenerative-dystrophic changes in the CS, especially in case of subcompensation of CBI. 2. Psychoemotional changes were a characteristic feature of patients with VD against the background of CBI and had certain regularities depending on the phase of CBI. 3. Suffered coronavirus infection contributes to the progression of VD and further decompensation of CBI due to direct damage to the autonomic and vascular systems of the brain. 4. Changes in cerebral hemodynamics in the form of reduced perfusion in BA and VA, a decrease in cerebrovascular reactivity, and an increase in reactivity to rotational functional load were determined in patients with VD against the background of subcompensated CBI.

Vegetative and cerebrovascular regulation in vestibular dysfunctions of ischemic origin

Vestibular dysfunction (VD) is a common syndrome of ischemic brain damage that occurs with pronounced vegetative accompaniment, cerebrovascular regulation disorder. 62 patients with VD on the background of chronic brain ischemia in the compensated (I group n = 24) and subcompensated (II group n = 38) stages were examined (40.3 % men; 59.7 % women), age from 18 to 55 years, average age was 38.6 ± 1.6 years. In case of ischemic damage to the brain due to degenerative-dystrophic changes in the cerebral cortex, certain mechanisms of the development of VD with dizziness have been registered. Their presence in the clinical picture of vascular dyshemia correlates with the degree of damage, is ac- companied by pain, as well as associated complaints and symptoms. Vestibulo-atactic disorders, recorded using the integrative state of statolocomotor, were elevated compared to healthy subjects, and further increased depending on the degree of brain damage, especially against the background of prevailing vagotonia in most patients. Autonomic dysfunctions are an important aspect of the development of VD. The obtained data indicate that VD develops against the background of pathological autonomic characteristics with predominant parasympathetic orientation of vegetative tone, especially in the case of insufficiency of vegetative reactivity and pathological vegetative maintenance of activity. Such changes significantly (p &lt; 0.05) increased in the presence of subcompensation of the chronic brain ischemia. Psychoemotional and cognitive disorders are comorbid according to the changed autonomic characteristics in VD on the background of chronic brain ischemia with initial patterns depending on the degree of brain damage. A characteristic hemodynamic feature in the groups with compensated and subcompensated chronic brain ischemia is the presence of reduced perfusion in main artery and vertebral artery. Significant changes in cerebral vascular reactivity along the myogenic circuit with a decrease in KrO2 and KrFNT indicators are a characteristic feature of the subcompensated stage of chronic brain ischemia. Hyperreactivity on rotational functional loads in both clinical groups has a high correlation with the presence of staircase and, to a lesser extent, isolated instability.

Retinal vascular changes in response to hypoxia

AbstractPurpose: Increased tortuosity and engorgement of retinal vasculature are recognized physiological responses to hypoxia. This can lead to high‐altitude retinopathy (HAR), which is a pathology seen in unacclimatised individuals at altitude. It typically features asymptomatic flame haemorrhages, but incidence reports are highly variable and our understanding of the aetiological mechanisms remains incomplete. This study aimed to evaluate retinal vascular changes throughout an expedition to 4167 metres.Methods: 10 healthy participants summitted Mount Toubkal, Morocco. Fundus images were taken on a handheld camera pre‐departure, daily throughout the expedition, and one‐month post‐return. Diameter and tortuosity of four vessels was assessed, in addition to vessel density and the presence of HAR.Results: Significant (p ≤ 0.05) increases in tortuosity and diameter were observed in some vessels on high‐altitude exposure days. There was a significant increase in vessel density on summit day only.Conclusions: This is the first study to report increased vessel density and no incidence of HAR. These results are likely attributable to relatively low altitude exposure, a conservative ascent profile, and the young, healthy demographic profile of participants. However, the study is limited by its small sample size, environmental confounding factors and semi‐subjective diameter measurements. Physiological but not pathological changes were seen in this cohort, which gives insight to the state of the cerebral vasculature throughout this expedition and builds on current understanding of retinal vascular changes in hypoxia. Future work must include daily retinal images of larger sample sizes at higher altitude and take steps to mitigate against environmental confounders. This work is relevant to altitude tourists, patients with diabetic retinopathy or retinal vein occlusion, and critically ill patients at sea level.

Abstract 15318: Global Deletion of P90 Ribosomal S6 Kinase Provides Cardiovascular Protection Against Age-Related Hypertension

Background: Hypertension (HT) is highly prevalent and associated with significant mortality and morbidity among older individuals. Aging is associated with structural and functional remodeling of the vasculature, similar to blood vessel alterations observed in HT. We previously demonstrated that young adult global Rsk2 KO mice had more dilated mesenteric arteries (MAs), with reduced vessel tone, stiffness and RLC 20 phosphorylation, and significantly lower basal blood pressure compared to WT. However, it is unknown whether RSK2 plays a role in age-related HT. Hypothesis: Loss of RSK2 signaling in aged mice inhibits age-related- and L-NAME-induced HT, arterial stiffness, and vascular remodeling. Methods: Systolic blood pressure (SBP) measurements of &gt;24-month-old global Rsk2 KO and WT males were performed daily for 2 weeks after 2 weeks of daily training using tail cuff manometry. Baseline echocardiographic (echo) parameters were measured. N(G)-Nitro-L-arginine-methyl ester (L-NAME) was administered (20 mg/kg/day) via drinking water to induce HT. Pressure myography studies assessed vascular reactivity and arterial stiffness in MAs isolated from Rsk2 KO and WT mice. Aorta and MAs were sectioned and stained to examine structural changes. Results: WT mice had a significantly higher mortality rate (63.6%) compared to Rsk2 KO (12.5%). Baseline SBP was also significantly higher in WT compared to KOs (123±10 vs. 99±12 mmHg, p &lt; 0.001, n = 9/7). L-NAME elevated SBP in WT but not in KO mice (137±2 vs. 97±8 mmHg, p &lt; 0.00001, n = 4/7). Although there were no differences in echo parameters, we observed a negative correlation between ejection fraction (EF) and SBP in WT (-0.94 %/mmHg, p = 0.046, R 2 = 0.59, n = 6), but not in Rsk2 KO mice (p = 0.15, n = 7). Functional and histological studies in aged KO mice are ongoing to examine age-related changes in vascular reactivity and remodeling. Conclusion: Loss of RSK2 reduces BP levels in aged mice akin to young adult mice. Additionally, the hypertensive effects of L-NAME are absent in aged Rsk2 KO mice. Aged Rsk2 KO mice appear to be protected from cardiovascular effects associated with age-related HT. Therapeutic targeting of RSK2 could prove beneficial for reducing risk of cardiovascular diseases associated with HT in the elderly.

Effects of aromatase inhibitor therapy on visceral adipose tissue area and cardiometabolic health in postmenopausal women with early and locally advanced breast cancer.

Aromatase inhibitor (AI) therapy provides oncological benefits in postmenopausal women with oestrogen receptor-positive breast cancer. However, AI treatment has been associated with increased cardiovascular risk. In nonbreast cancer populations, experimentally induced low oestrogen states and natural transition to menopause have been associated with increases in visceral adipose tissue (VAT), a known surrogate marker for cardiometabolic risk. Given that AI treatment blocks oestradiol production, we hypothesized that AI treatment would increase VAT. We conducted a prospective 12-month cohort study of 52 postmenopausal women newly initiating AI treatment (median age: 64.5 years) and 52 women with breast pathology not requiring endocrine therapy (median age: 63.5 years). VAT area and other body composition parameters were measured at baseline, 6months and 12 months using dual X-ray absorptiometry. Other risk markers of cardiometabolic health were also assessed. In women initiating AI treatment, there was no statistically significant difference in VAT area after 12 months when compared to controls, with a mean adjusted difference of -5.00 cm2 (-16.9, 6.91), p = .55. Moreover, changes in total fat mass, lean mass, subcutaneous adipose tissue area, hepatic steatosis and measures in endothelial function were also not statistically different between groups after 12 months. Findings were similar after adjustments for activity levels and coronavirus disease 2019 lockdown duration. These data provide reassurance that over the initial 12 months of AI therapy, AI treatment is not associated with metabolically adverse changes in body composition, hepatic steatosis or vascular reactivity. The impact of extended AI therapy on cardiometabolic health requires further study.

Endothelial dysfunction of the mesenteric arteries of rats in the early obesity induced by high-fat diet

Background: Disturbance of the morphological and functional properties of the vascular bed in obesity are a serious clinical problem. Basis to their development is endothelial dysfunction. The developed models of obesity in animals using various diets indicate a change in vascular reactivity, however, questions about the stage at which this occurs and what mechanisms are involved in this process remain open, while they are decisive for choosing the correct tactics for correcting dysfunctions.Aim: The aim of the present study is to determine the changes in acetylcholine (ACh)-induced vasodilation of isolated arteries from rats after six weeks of administration of a high-fat diet (HFD).Materials and methods: The experiments were performed on Sprague-Dawley males, which at the age of 8 weeks were divided into 2 experimental groups that were treated for the next 6 weeks in the following manner: 1 - control) with standard dry food; 2 - a group fed with a HFD, the total amount of fat in which was 50%. At finish of the diet, the degree of obesity, biochemical parameters in the blood, and blood pressure were measured. Intravital microscopy of the rat mesentery with video recording was used to study the reactivity of the vessels. The contractile and relaxant responses of the vessels were determined by changes in their diameter.Results: The rats after treatment with the HFD (n=15) had higher body weight and amount of visceral fat, significantly increased blood triglycerides, moderate increases in glucose level in blood and systolic pressure compared with the control (n=15). Relaxation responses of mesenteric arteries, having a diameter of 140 to 300 μm in PSS, were recorded after precontraction by phenylephrine. A decrease in ACh-induced vasorelaxation was obtained, which manifests itself before the development of significant changes in carbohydrate metabolism. Incubation of drugs with the inhibitor of endothelial NO synthase L-NAME led to a pronounced weakening of relaxation in animals on a standard diet, and had little effect on vasodilation in the arteries of rats with the HFD. Vasodilation induced by the administration of sodium nitroprusside (NO donor) did not differ significantly in control and experimental animals, which indicates that the sensitivity of vascular smooth muscle to NO remained practically unchanged. ACh-induced relaxation of arteries in dietary rats did not change when the cyclooxygenase pathway was blocked by diclofenac.Conclusion: Functional changes in the contractile activity of the mesenteric arteries, manifested in the form of a decrease in ACh-induced vasorelaxation, occur after treatment with the HFD when animals had an early stage of obesity development before the onset of pronounced disorders of carbohydrate metabolism. This decrease is mainly due to the disruption of the NO-dependent mechanism underlying ACh-induced relaxation in the norm.

Effect of fenofibrate on biochemical and vascular reactivity changes in aged rats

Effect of fenofibrate on biochemical and vascular reactivity changes in aged rats