Arteriolar Diameter Research Articles

Retinal blood vessel diameter changes with 60-day head-down bedrest are unaffected by antioxidant nutritional cocktail.

Long-term human spaceflight can lead to cardiovascular deconditioning, but little is known about how weightlessness affects microcirculation. In this study, we examined how the retinal microvessels and cerebrovascular regulation of 19 healthy male participants responded to long-term head-down bedrest (HDBR), an earth-based analog for weightlessness. In addition, we examined whether an anti-inflammatory/antioxidant cocktail could prevent the vascular changes caused by HDBR. In all study participants, we found a decrease in retinal arteriolar diameter by HDBR day 8 and an increase in retinal venular diameter by HDBR day 16. Concurrently, blood pressure at the level of the middle cerebral artery and the cerebrovascular resistance index were higher during HDBR, while cerebral blood flow velocity was lower. None of these changes were reversed in participants receiving the anti-inflammatory/antioxidant cocktail, indicating that this cocktail was insufficient to restore the microvascular and cerebral blood flow changes induced by HDBR.

Glomerular pressure and tubular oxygen supply: a critical dual target for renal protection.

The primary treatment goal of chronic kidney disease (CKD) is preserving renal function and preventing its progression to end-stage renal disease. Glomerular hypertension and tubular hypoxia are critical risk factors in CKD progression. However, the renal hemodynamics make it difficult to avoid both factors due to the existence of peritubular capillaries that supply oxygen to the renal tubules downstream from the glomerulus through the efferent arteriole. In the treatment strategies for balancing glomerular pressure and tubular oxygen supply, afferent and efferent arterioles of the glomerulus determine glomerular filtration rate and blood flow to the peritubular capillaries. Therefore, sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors as well as classical renin-angiotensin system inhibitors, which can change the diameter of afferent and/or efferent arterioles, are promising options for balancing this dual target and achieving renal protection. This review focuses on the clinical importance of glomerular pressure and tubular oxygen supply and proposes an effective treatment modality for this dual target.

L-Arginine and Taurisolo® Effects on Brain Hypoperfusion-Reperfusion Damage in Hypertensive Rats.

Acute and chronic hypertension causes cerebral vasculopathy, increasing the risk of ischemia and stroke. Our study aimed to compare the effects of arterial pressure reduction on the pial microvascular responses induced by hypoperfusion and reperfusion in spontaneously hypertensive Wistar rats, desamethasone-induced hypertensive Wistar rats and age-matched normotensive Wistar rats fed for 3 months with a normal diet or normal diet supplemented with L-arginine or Taurisolo® or L-arginine plus Taurisolo®. At the end of treatments, the rats were submitted to bilateral occlusion of common carotid arteries for 30 min and reperfusion. The microvascular parameters investigated in vivo through a cranial window were: arteriolar diameter changes, permeability increase, leukocyte adhesion to venular walls and percentage of capillaries perfused. Hypoperfusion-reperfusion caused in all rats marked microvascular changes. L-arginine treatment was effective in reducing arterial blood pressure causing vasodilation but did not significantly reduce the damage induced by hypoperfusion-reperfusion. Taurisolo® treatment was less effective in reducing blood pressure but prevented microvascular damage from hypoperfusion-reperfusion. L-arginine plus Taurisolo® maintained blood pressure levels within the physiological range and protected the pial microcirculation from hypoperfusion-reperfusion-induced microvascular injuries. Therefore, the blood pressure reduction is not the only fundamental aspect to protect the cerebral circulation from hypoperfusion-reperfusion damage.

Changes in morphometric indicators of liver blood vessels under conditions of long-term ethanol exposure

Hyperdynamic splanchnic blood circulation is an important component of portal hypertension syndrome, which develops under conditions of chronic alcoholic hepatitis. Angiogenesis caused by alcohol consumption contributes to the development of splanchnic hyperemia and the development of portal-systemic collaterals. The purpose of the study is to study the morphometric indicators of the vascular bed of the liver of rats under the conditions of chronic alcoholic hepatitis modeling. Experiments were performed on 30 white, sexually mature male Wistar rats weighing 180–220 g. The animals were divided into 2 groups: I (control group) contained 6 rats; II – 24 rats that modeled chronic alcoholic hepatitis by the method of forced intermittent alcoholization for 5 days, with a repeat after two days by intraperitoneal injection of a 16.5% ethanol solution in a 5.0% glucose solution, at the rate of 4 ml/kg of body weight. Animals were removed from the experiment on days 35, 42, 49, and 56 by taking blood from the right ventricle of the heart under thiopental anesthesia. On the 35th day of simulation of chronic alcoholic hepatitis, the inner diameter of central veins, lobular arterioles and interlobular veins increased, and interlobular arteries and lobular venules decreased compared to the control. On the 42nd day of simulation of chronic alcoholic hepatitis, the internal diameter of central veins, lobular arterioles and interlobular veins increased, and interlobular arteries decreased compared to the control. On the 49th day of simulation of chronic alcoholic hepatitis, the inner diameter of the central veins, lobular arterioles, and interlobular veins increased, and the interlobular arteries decreased compared to the control. On the 56th day of simulation of chronic alcoholic hepatitis, the inner diameter of the central veins and lobular arterioles increased, and the interlobular arteries and lobular venules decreased compared to the control. Keywords: arteries, veins, arterioles, venules, sinusoidal capillaries.

Characterizing Vascular Wall and Lumen Caliber in Eyes with Diabetic Retinopathy Based on Adaptive Optics Scanning Laser Ophthalmoscopy.

Each study eye underwent mydriasis and AOSLO imaging in a single-visit study. The instrument's arrangement of four offset aperture images provided two orthogonal split-detector images and enabled isotropic analysis of the arteriolar boundaries. For each arteriole, we calculated the wall-to-lumen ratio (WLR), mean wall thickness, and luminal and external diameters. In total, we enrolled 5 (20.8%) healthy control eyes and 19 eyes of patients with T1D. The DR distribution was: four (16.7%) no-DR, nine (37.5%%) mild or moderate nonproliferative DR (NPDR), and six (25%) severe NPDR or proliferative DR. Mean wall thickness increased significantly in eyes with T1D compared to healthy controls (p = 0.0006) and in eyes with more advanced DR (p = 0.0004). The WLR was significantly higher in eyes with T1D (p = 0.002) or more severe DR (p = 0.004). There was no significant relationship between T1D status or DR severity and any of the arteriolar diameters. In this preliminary study, there appeared to be increases in the WLR and mean wall thickness in eyes with T1D and more severe DR than in the controls and eyes with no/less severe DR. Future studies may further elucidate the relationship between the retinal arteriolar structure and physiologic alterations in DR.

Sparsentan improves glomerular hemodynamics, cell functions, and tissue repair in a mouse model of FSGS.

Dual endothelin-1 (ET-1) and angiotensin II (AngII) receptor antagonism with sparsentan has strong antiproteinuric actions via multiple potential mechanisms that are more pronounced, or additive, compared with current standard of care using angiotensin receptor blockers (ARBs). Considering the many actions of ET-1 and AngII on multiple cell types, this study aimed to determine glomeruloprotective mechanisms of sparsentan compared to the ARB losartan by direct visualization of its effects in the intact kidney in focal segmental glomerulosclerosis (FSGS) using intravital multiphoton microscopy. In both healthy and FSGS models, sparsentan treatment increased afferent/efferent arteriole diameters; increased or preserved blood flow and single-nephron glomerular filtration rate; attenuated acute ET-1 and AngII-induced increases in podocyte calcium; reduced proteinuria; preserved podocyte number; increased both endothelial and renin lineage cells and clones in vasculature, glomeruli, and tubules; restored glomerular endothelial glycocalyx; and attenuated mitochondrial stress and immune cell homing. These effects were either not observed or of smaller magnitude with losartan. The pleiotropic nephroprotective effects of sparsentan included improved hemodynamics, podocyte and endothelial cell functions, and tissue repair. Compared with losartan, sparsentan was more effective in the sustained preservation of kidney structure and function, which underscores the importance of the ET-1 component in FSGS pathogenesis and therapy.

Vascular function in patients with advanced heart failure and continuous-flow or pulsatile ventricular assist devices.

A significant proportion of patients with heart failure (HF) progress to an advanced stage, which is associated with a substantial increase in morbidity and mortality. These patients may be eligible for advanced treatment strategies such as mechanical circulatory support with ventricular assist devices (VAD). Vascular dysfunction is a hallmark of heart failure pathophysiology and prognosis. However, whether and to what degree the hemodynamic benefits of VADs influence vascular function remain unknown. In this study, we evaluated endothelial vascular function with flow-mediated vasodilatation (FMD) and with flicker-light induced retinal vasodilatation (FID). 34 patients with a VAD (age 58 ± 10years, 85% male, 74% ischemic heart disease, 26 continuous-flow (CF)-LVAD, and 8 pulsatile biventricular (bi)-VAD) were compared to 34 propensity-matched patients (mean age 62 ± 9years, 68% male, 59% ischemic heart disease) with advanced HF (AdvHF). Endothelial function of larger arteries (FMD) was significantly better in patients after VAD implantation compared to matched AdvHF patients (7.2 ± 4.6% vs. 5.0 ± 3.2%, p = 0.03), whereas microvascular arteriolar function (FIDart) did not differ (0.99 ± 1.43% vs. 1.1 ± 1.7%, p = 0.78). The arterio-venous ratio (AVR) was higher in the VAD group (0.90 ± 0.06 vs 0.85 ± 0.09, p = 0.01), reflecting wider retinal arteriolar and narrower venular diameters. There was no difference in vascular function between patients with CF-LVAD and pulsatile Bi-VAD. In patients with advanced heart failure, VAD implantation was associated with better endothelial function at the level of large arteries, but not in the microcirculation.

Ninjin'yoeito Modulates Baseline and Reperfusion-Induced Changes in the Arteriole Diameter and Blood Flow in the Cerebral Cortex of Anesthetized Mice.

Intragastric administration of ninjin'yoeito (NYT), a traditional Japanese herbal medicine, reportedly prevents the decrease in baseline cerebral blood flow (CBF) in the cortex following gastric administration of water. We investigated the effect of NYT on baseline and dynamic changes in cerebral cortical arteriole diameter. Urethane-anesthetized mice were intragastrically administered 1 g/kg NYT or distilled water (DW). The artery in the left parietal cortex was imaged using two-photon microscopy. The baseline diameter of penetrating arterioles was measured before and 50-60 min after administration. Dynamic CBF and arteriole diameter changes before, during, and after transient occlusion of the left common carotid artery were measured approximately 10 min after administration. DW decreased the baseline diameter of the penetrating arterioles, whereas NYT did not. During occlusion, the increase in penetrating arteriole diameter was comparable for DW and NYT; however, during reperfusion, the return to preocclusion diameter was slower for NYT than DW. Laser-speckle contrast imaging confirmed that CBF, although comparable during occlusion, was higher during reperfusion for NYT than DW. These results suggest that NYT attenuates vasoconstriction in penetrating arterioles after intragastric administration and during cerebral reperfusion, contributing to CBF regulation.

Effect of Continuous Positive Airway Pressure Treatment on the Arteriole-to-Venule Ratio in Patients With Nonproliferative Diabetic Retinopathy and Obstructive Sleep Apnea: A Randomized Trial.

This study aimed to assess the effect of continuous positive airway pressure (CPAP) on the arteriolar-to-venular ratio (AVR) in patients with diabetic retinopathy (DR) and obstructive sleep apnea (OSA). A prospective, randomized, unblinded, and controlled clinical trial with parallel groups was performed. From a base of 138 patients, 83 were randomized to either CPAP or control. Nonstereoscopic 35º photographs were processed with Sirius software. The intention-to-treat analysis showed no differences in AVR, although the arteriolar diameter increased from baseline in the CPAP group. Per-protocol analysis showed a 12-month increase in AVR (P = 0.035) and arteriolar diameter (P = 0.033) in CPAP versus control group. The venular diameter showed a nonstatistically significant reduction. CPAP is a potentially novel treatment for individuals with DR and concomitant OSA, improving the retinopathy status, reversing the arteriolar narrowing, and therefore increasing the AVR, tending to reduce the venular diameter. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Stress-induced impairment of parasympathetic NO-mediated inhibition of sympathetic vasoconstriction in submucosal arteriole of rat rectum.

In the gastrointestinal tract, nitrergic inhibition of the arteriolar contractility has not been demonstrated. Here, we explored whether neurally-released nitric oxide (NO) inhibits sympathetic vasoconstrictions in the rat rectal arterioles. Changes in sympathetic vasoconstrictions and their nitrergic modulation in rats exposed to water avoidance stress (WAS, 10days, 1h per day) were also examined. In rectal submucosal preparations, changes in arteriolar diameter were monitored using video microscopy. In control or sham-treated rats, electrical field stimulation (EFS)-induced sympathetic vasoconstrictions were increased by the neuronal nitric oxide synthase (nNOS) inhibitor L-NPA (1μM) and diminished by the cyclic guanosine monophosphate-specific phosphodiesterase 5 (PDE5) inhibitor tadalafil (10nM). In phenylephrine-constricted, guanethidine-treated arterioles, EFS-induced vasodilatations were inhibited by the calcitonin gene-related peptide (CGRP) receptor antagonist BIBN-4096 (1μM) but not L-NPA. Perivascular nNOS-immunoreactive nitrergic fibres co-expressing the parasympathetic marker vesicular acetylcholine transporter (VAChT) were intermingled with tyrosine hydroxylase (TH)-immunoreactive sympathetic fibres expressing soluble guanylate cyclase (sGC), a receptor for NO. In WAS rats in which augmented sympathetic vasoconstrictions were developed, L-NPA failed to further increase the vasoconstrictions, while tadalafil-induced inhibition of the vasoconstrictions was attenuated. Phenylephrine- or α,β-methylene ATP-induced vasoconstrictions and acetylcholine-induced vasodilatations were unaltered by WAS. Thus, in arterioles of the rat rectal submucosa, NO released from parasympathetic nerves appears to inhibit sympathetic vasoconstrictions presumably by reducing sympathetic transmitter release. In WAS rats, sympathetic vasoconstrictions are augmented at least partly due to the diminished pre-junctional nitrergic inhibition of transmitter release without changing α-adrenoceptor or P2X-purinoctor mediated vasoconstriction and endothelium-dependent vasodilatation.

Randomized 20-year infancy-onset dietary intervention, life-long cardiovascular risk factors and retinal microvasculature.

Retinal microvasculature characteristics predict cardiovascular morbidity and mortality. This study investigated associations of lifelong cardiovascular risk factors and effects of dietary intervention on retinal microvasculature in young adulthood. The cohort is derived from the longitudinal Special Turku Coronary Risk Factor Intervention Project study. The Special Turku Coronary Risk Factor Intervention Project is a 20-year infancy-onset randomized controlled dietary intervention study with frequent study visits and follow-up extending to age 26 years. The dietary intervention aimed at a heart-healthy diet. Fundus photographs were taken at the 26-year follow-up, and microvascular measures [arteriolar and venular diameters, tortuosity (simple and curvature) and fractal dimensions] were derived (n = 486). Cumulative exposure as the area under the curve for cardiovascular risk factors and dietary components was determined for the longest available time period (e.g. from age 7 months to 26 years). The dietary intervention had a favourable effect on retinal microvasculature resulting in less tortuous arterioles and venules and increased arteriolar fractal dimension in the intervention group when compared with the control group. The intervention effects were found even when controlled for the cumulative cardiovascular risk factors. Reduced lifelong cumulative intake of saturated fats, main target of the intervention, was also associated with less tortuous venules. Several lifelong cumulative risk factors were independently associated with the retinal microvascular measures, e.g. cumulative systolic blood pressure with narrower arterioles. Infancy-onset 20-year dietary intervention had favourable effects on the retinal microvasculature in young adulthood. Several lifelong cumulative cardiovascular risk factors were independently associated with retinal microvascular structure.

Longitudinal associations of retinal vessel morphology with intraocular pressure and blood pressure at follow-up visit-Findings from a Danish eye and vision cohort, Project FOREVER.

To characterise the retinal vasculometry of a Danish eye and vision cohort and examine associations with systolic blood pressure (BP), diastolic BP, mean arterial BP, and intraocular pressure (IOP). Longitudinal study. The retinal vasculature of fundus images from the FOREVER (Finding Ophthalmic Risks and Evaluating the Value of Eye exams and their predictive Reliability) cohort was analysed using a fully automated image analysis program. Longitudinal associations of retinal vessel morphology at follow-up visit with IOP (baseline and follow-up) and BP (follow-up) were examined using multilevel linear regression models adjusting for age, sex and retinal vasculometry at baseline as fixed effects and person as random effect. Width measurements were additionally adjusted for the spherical equivalent. A total of 2089 subjects (62% female) with a mean age of 61 (standard deviation 8) years and a mean follow-up period of 4.1 years (SD 0.6 years) were included. The mean arteriolar diameter was approximately 20% thinner than the mean venular diameter, and venules were about 21%-23% less tortuous than arterioles. BP at follow-up was associated with decreased arteriolar diameter from baseline to follow-up. After adjusting for baseline IOP, IOP at follow-up was associated with increased arteriolar tortuosity above baseline (0.59%, 95% CI 0.08-1.10, p-value 0.024). In a Danish eye and vision cohort, variations in BP and alterations in IOP over time were associated with changes in the width and tortuosity of retinal vessels. Our findings contribute novel insights into retinal vascular alterations over time.

Influence of nuclear factor κB and adenosine monophosphate-activated protein kinase on the vascular bed of the liver under the conditions of modeling chronic alcoholic hepatitis

Chronic alcohol use activates the transcription factor κB (NF-κB) in liver sinusoidal endothelial cells (LSECs), macrophages and other cells of the liver parenchyma, which controls the regulation of the expression of pro-inflammatory cytokines that activate signaling pathways of immune regulation of liver inflammation and vascular tone. AMP-activated protein kinase (AMPK) is an important immunometabolic regulatory factor in macrophages and, as a metabolic sensor, AMPK in vascular cells may be involved in the regulation of blood flow. The aim of the work was to find out the effect of modulators of the transcription factor κB and AMP-activated protein kinase on the morphometric parameters of the vascular bed of the liver of rats under the conditions of modeling chronic alcoholic hepatitis. Simulation of chronic alcoholic hepatitis leads to a violation of the exchange of metabolites between the central and interlobular veins, which creates prerequisites for the development of hypoxic damage to hepatocytes, as evidenced by a decrease in the diameters of lobular arterioles and venules. Administration of ammonium pyrrolidinedithiocarbamate and bacterial lipopolysaccharide, which affect NF-κB signaling under the conditions of modeling chronic alcoholic hepatitis, helps to restore the exchange of metabolites between the central and interlobular veins, which is evidenced by an increase in the lumens of lobular arterioles and venules. The introduction of phenformin and doxorubicin, which affect AMPK under the conditions of modeling chronic alcoholic hepatitis, prevents the development of hypoxic damage to hepatocytes, as evidenced by an increase in the diameters of lobular arteries and veins, and leads to intensification of interlobular blood circulation.

Endothelial dysfunction in retinal vessels of hemodialysis patients compared to healthy controls

Endothelial dysfunction is a key factor promoting atherosclerosis and cardiovascular complications. Hemodialysis patients typically show various cardiovascular complications and impaired retinal venular dilation has been described as a risk factor for mortality. Non-invasive retinal vessel analysis provides insight into the microvasculature and endothelial function. Static retinal vessel analysis determines arteriolar and venular vessel diameters and dynamic retinal vessel analysis measures microvascular function by flicker-light induced stimulation, which results in physiological dilation of retinal vessels. We measured 220 healthy individuals and compared them to our preexisting cohort of hemodialysis patients (275 for static and 214 for dynamic analysis). Regarding static vessel diameters, hemodialysis patients and healthy individuals did not significantly differ between vessel diameters. Dynamic retinal vessel analysis showed attenuated dilation of the arteriole of hemodialysis patients with 1.6% vs 2.3% in healthy individuals (p = 0.009). Case–control matching for age (mean 65.4 years) did not relevantly diminish the difference. Hemodialysis patients also exhibited reduced venular dilation after matching for age (3.2% vs 3.8%, p = 0.019). Hemodialysis patients showed microvascular dysfunction compared to healthy individuals when using dynamic retinal vessel analysis. Further studies should focus on dynamic retinal vessel analysis which can add insights into the microvascular function and risk factors in multimorbid patients.

Anatomy of blood microcirculation in the pig epicardial ganglionated nerve plexus

Embolization of coronary arteries and their terminal arterioles causes ischemia of all tissues distributed within a cardiac wall including the intrinsic cardiac ganglionated nerve plexus (ICGP). The disturbed blood supply to the ICGP causes chronic sympathetic activation with succeeding atrial and ventricular arrhythmias. This study analyses the anatomy of microcirculation of epicardial nerves and ganglia using the hearts of 11 domestic pigs. Our findings demonstrate that thicker epicardial nerves are normally supplied with blood via 12 epineural arterioles penetrating the endoneurium regularly along a nerve, and forming an endoneurial capillary network, which drains the blood into the myocardial blood flow. The mean diameter of intraneural capillaries was 7.2 ± 0.2 µm, while the diameters of arterioles were 25.8 ± 0.7 μm and involved 45 endothelial cells accompanied by circular smooth muscle cells. Usually, two or three arterioles with a mean diameter of 28.9 ± 1.7 μm supplied blood to any epicardial ganglion, in which arterioles proceeded into a network of capillaries with a mean diameter of 6.9 ± 0.3 μm. Both the epicardial nerves and the ganglia distributed near the porta venarum of the heart had tiny arterioles that anastomosed blood vessels from the right and the left coronary arteries. The density of blood vessels in the epicardial nerves was significantly lesser compared with the ganglia. Our electron microscopic observations provided evidence that blood vessels of the pig epicardial nerves and ganglia may be considered as either arterioles or capillaries that have quantitative and qualitative differences comparing to the corresponding blood vessels in humans and, therefore, a pig should not be considered as an animal model of the first choice for further heart functional studies seeking to improve the treatment of cardiac arrhythmias via trans-coronary cardiac neuroablation. Structured abstractThis study details the anatomy of microcirculation of epicardial nerves and ganglia, from which intracardiac nerves and bundles of nerve fibers extend into all layers of the atrial and ventricular walls in the most popular animal model of experimental cardiology and cardiac surgery - the domestic pig. Our findings provided evidence that blood vessels of the pig epicardial nerves and ganglia may be considered as either arterioles or capillaries that have quantitative and qualitative differences comparing to the corresponding blood vessels in humans and, therefore, a pig should not be considered as an animal model of the first choice for further heart functional studies seeking to improve the treatment of cardiac arrhythmias via trans-coronary cardiac neuroablation.

Evaluation of glomerular hemodynamic changes by sodium-glucose-transporter 2 inhibition in type 2 diabetic rats using in vivo imaging

The mechanisms responsible for glomerular hemodynamic regulation with sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney disease due to type 2 diabetes remain unclear. Therefore, we investigated changes in glomerular hemodynamic function using an animal model of type 2 diabetes, treated with an SGLT2 inhibitor alone or in combination with a renin-angiotensin-aldosterone system inhibitor using male Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Afferent and efferent arteriolar diameter and single-nephron glomerular filtration rate (SNGFR) were evaluated in ZDF rats measured at 0, 30, 60, 90, or 120 minutes after the administration of a SGLT2 inhibitor (luseogliflozin). Additionally, we assessed these changes under the administration of the adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine), along with coadministration of luseogliflozin and an angiotensin II receptor blocker (ARB), telmisartan. ZDF rats had significantly increased SNGFR, and afferent and efferent arteriolar diameters compared to ZL rats, indicating glomerular hyperfiltration. Administration of luseogliflozin significantly reduced afferent vasodilatation and glomerular hyperfiltration, with no impact on efferent arteriolar diameter. Urinary adenosine levels were increased significantly in the SGLT2 inhibitor group compared to the vehicle group. A1aR antagonism blocked the effect of luseogliflozin on kidney function. Co-administration of the SGLT2 inhibitor and ARB decreased the abnormal expansion of glomerular afferent arterioles, whereas the efferent arteriolar diameter was not affected. Thus, regulation of afferent arteriolar vascular tone via the A1aR pathway is associated with glomerular hyperfiltration in type 2 diabetic kidney disease.

A brain vascular electrical network links capillary pericytes to arterioles and is recruited for neurovascular coupling

The brain has evolved mechanisms to rapidly modify local vascular resistance near active neurons. This enables delivery of energy substrates and clearance of byproducts via the blood to meet the energetic demands of circuits engaged during cognitive and motor tasks. Collectively, the physiochemical processes governing the spatially precise blood flow changes that accompany neural activity are termed “neurovascular coupling”. Crucially, these blood flow changes are leveraged by functional brain imaging techniques in humans to evaluate disease processes and understand cognition. It is therefore imperative to understand in detail the interaction between neurons and vasculature in the brain. While several neurovascular coupling pathways have been identified and studied, there is still no consensus on the vascular signal transduction and transmission mechanisms that enable acute responses to vasoactive substances released by active neurons. Arteriolar diameter is viewed as a crucial control point for neurovascular coupling. The relatively sparse spatial arrangement of arterioles contrasts with the vast plexus of capillaries, suggesting that that the latter is well positioned to play a major role in sensing neural activity and transmitting signals to modify the state of contractile cells on upstream vessels. Thin-strand pericyte processes cover a large fraction of the capillary bed but the contributions of these cells to blood flow control are not understood and are controversial. Here, we provide evidence that thin strand pericytes in the deep capillary bed play a role in neurovascular coupling by sensing neural activity and rapidly relaying electrical signals to arterioles. We identify a KATP channel-dependent neurovascular signaling pathway that can be explained by the recruitment of capillary pericytes. We developed a vascular optogenetics approach to show that membrane currents generated in single thin-strand pericytes are rapidly sent over long distances to penetrating arterioles in vivo. We demonstrate that genetic disruption of the KATP channel reduces the neurovascular coupling arteriole diameter response and laser ablation of pericytes eliminates KATP-dependent neurovascular coupling. Overall, our work suggests that the thin-strand pericytes of the capillary bed actively sense neural activity and integrate this into electro metabolic signals that inform arterioles of local energy needs ensuring spatiotemporal specificity in the availability of energy substrates like glucose, lactate, and oxygen. This work was supported by the NIH T32 Interdisciplinary Training Program in Cardiovascular Disease at The University of Maryland School of Medicine (ITCVD-T32), and NIH grants 1R01AG066645, 5R01NS115401, and 1DP2NS121347. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Microcirculatory Evaluation of Crystalloids, Fresh Frozen Plasma, Hemoglobin Based Oxygen Carriers, and Pack Red Blood Cells in Trauma Hemorrhagic Shock

Introduction: The prehospital management of traumatic injuries has significantly evolved since the establishment of emergency medical services in the 1970s. Initially focused on using crystalloid solutions, experiences in military and civilian trauma care have shifted towards balanced blood components for immediate blood replacement, known as remote damage control resuscitation (RDCR). This shift led to the adoption of prehospital transfusion, with packed red blood cells (pRBC) showing increased survival rates upon hospital arrival but no overall increase in survival. Additionally, fresh frozen plasma (FFP) and its timing of administration remain controversial. The development of hemoglobin-based oxygen carriers (HBOCs) aims to rival blood products, offering logistical advantages and potential to replace pRBC and FFP in challenging accessibility scenarios. This study investigates HBOCs' effcacy during hemorrhagic shock, hypothesizing their comparability to crystalloids, pRBC, and FFP in microcirculatory function. Methods:. To study the effcacy of HBOCs during hemorrhagic shock, Golden Syrian hamsters were instrumented with a dorsal window chamber, and catheters in the left common carotid artery, the animals were hemorrhaged for 50% of their blood volume (estimated as 7% of body weight) and resuscitated with 25% of their blood volume with LR, FP, HBOC, or pRBC. Shock was monitored for 30 minutes while resuscitation was monitored for 1 hour. Microvascular perfusion was characterized by vessel diameter, flow, and functional capillary density. Systemic variables were characterized as mean arterial pressure (MAP), heart rate (HR), and blood chemistry. Results: Across all animals, the baseline mean arterial pressure (MAP) and heart rate (HR) averaged 112.69 ± 11.16 mmHg and 404.44 ± 45.78 beats per minute (BPM), respectively. During shock, these values decreased to 50.76±11.57 mmHg and 379.36±60.49 BPM. Post-resuscitation using LR, FP, or HBOC, the MAP showed increases of 12%, 20%, and 44%, respectively. However, there were no significant changes observed in the HR. The HBOC group notably demonstrated the most substantial increase in MAP following shock. Arteriole diameter, both less than and greater than 60 μm, did not reveal any statistically significant differences between the HBOC group, except for the pRBC group, which showed larger diameters than the HBOC group after an hour post-resuscitation in arterioles < 60 μm. The arteriole flow in the HBOC group averaged a flow rate of 2.42 nL/s, compared to LR (0.13 nL/s), FP (1.30 nL/s), and pRBC (3.64 nL/s) in arterioles > 60 after an hour post-resuscitation, showing similar statistically significant differences in the HBOC group after the 60-minute post-resuscitation period. Conclusion: HBOCs exhibit promising potential as a resuscitation fluid for immediate blood replacement, not only due to their logistical advantages over blood component therapy but also for their ability to maintain more stable MAPs and better blood flow through small arterioles compared to component therapies. Project number: R01HL159862 Project number: R01HL162120. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Differential Role for the Clock Gene, BMAL1, on Kidney Function in Male versus Female Rats

Many activities of modern life, such as social visits with friends at night, long working hours, jet lag, and shift work cause circadian rhythm disturbances, which increase the risk of renal decline and eventual disease. Chronic kidney disease (CKD) is defined by decreases in glomerular filtration rate (GFR) which is higher during the daytime and lower at night in healthy individuals. Prior studies indicate that processes critical for maintaining blood pressure ( e.g. autoregulation) contribute to this time-of-day-dependence mediated by a molecular timekeeping mechanism known as the molecular circadian clock that resides in all tissues including the kidney. We hypothesized that loss of the molecular clock would impair normal kidney physiology through misalignment of functional rhythms with normal environmental patterns associated with day and night. We used a rat model of circadian disruption to interrogate our hypothesis. Male and female brain and muscle ARNT-like protein 1 knockout (BMAL1 KO) and littermate control (CON) rats aged 12-14 weeks underwent GFR measurements using FITC-labeled sinistrin clearance at two times of the day corresponding to the dark (active) and light (inactive) periods. Following GFR measurements, rats were placed in metabolic cages with food to record water intake and urine excretion over 12h active and inactive periods. Implantable telemeters were used for 24h measurement of systolic and diastolic blood pressure, locomotor activity and body temperature. Autoregulatory behavior was assessed using the isolated juxtamedullary nephron preparation to determine afferent arteriole diameter responses to changes in perfusion pressure. Diurnal measurements of GFR revealed that male BMAL1 KO rats had a significantly lower GFR in the active period as compared to CON males (1.87±0.37 vs 2.55±0.47 ml/min/100g; 2-way ANOVA, p<0.05; n=8-9). As a result, there was no diurnal variation in the KO males as seen in the CON males (Δ GFR 0.63±0.24 vs 0.04±0.21 ml/min/100g/12h CON vs KO respectively) (Sidak post-hoc, p<0.05; n=8-9) in parallel with a lack of diurnal variation in urine volume and Na excretion. Both male (n=8) and female (n=6-9) BMAL1 KO rats also displayed a significantly lower 24h mean arterial pressure (Males; 103±1 vs 107±1 mmHg, p<0.05; Females; 110±1 vs 100±2 mmHg, p<0.05) compared to CON with diurnal variation and autoregulatory reactivity preserved. Male BMAL1 KO rats consumed significantly more water compared to CON (n=5-9, 22.5±5.4 vs 14.7±4.0 mL/12h, p<0.05) concomitant with increased urine excretion (n=5-9, 13.3±6 vs 4.2±0.8 mL/12h, p<0.05) and reduced urine osmolality (n=5-7, 967±398 vs 2140±811 mmol/kg, p<0.05) regardless of time of day. Taken together these data suggest that BMAL1 is necessary for maintaining renal functional rhythms and urine concentrating ability in a sex-dependent manner. R01 DK134562 P01 HL158500. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A Hypovolemic Infusion of Human Methemoglobin in Golden Syrian Hamsters Provides Insight on its effect on the Microcirculation

Introduction: Hemoglobin (HbFe(II)) plays a crucial role in transporting oxygen to tissues for metabolic needs. However, this protein isn't just an oxygen carrier; it also regulates vascular tone and inflammation by its redox coupling with methemoglobin (HbFe(III)). Methemoglobin's oxidized form, Fe (III), possesses the potential to produce water from oxygen as a free energy reaction. It functions as a nitrite reductase, regulating the oxygen level in the blood and controlling vascular tone by generating nitric oxide from nitrite, thereby increasing blood flow when oxygenated hemoglobin decreases. If methemoglobin can't be reduced, it leads to the dissociation of tetrameric hemoglobin into αβ dimers, releasing heme and iron into circulation. Methods: The study involved Golden Syrian Hamsters with dorsal skin fold window chambers, observing acute methemoglobin effects via hypovolemic infusion (10% of the animal’s blood volume) compared to human hemoglobin and a lactated ringer's control. Microhemodynamics, mean arterial pressure, heart rate, blood gases, and blood properties were measured. Results: Methemoglobin did not significantly affect MAP and HR but increased arteriole diameters by 5% and venule diameter by 15% compared to baseline. However, it caused a 50% reduction in functional capillary density compared to baseline, alongside significant cardiac and kidney inflammation. Conclusion: The study concludes that a hypovolemic infusion of methemoglobin induces vasoreactivity but results in poor microcirculatory pressure and inflammation in vital organs. This demonstrates the delicate balance and potential adverse effects associated with alterations in the hemoglobin redox state and highlights the importance of maintaining its balance for vascular and organ health. Project number: R01HL159862 Project number: R01HL162120. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.