Precapillary Arterioles Research Articles

171-OR: Metformin Prevents Microvascular Insulin Resistance and Preserves Endothelial Function in High-Fat Diet-Fed Rats

Endothelial dysfunction and vascular insulin resistance coexist and both contribute to the development of type 2 diabetes mellitus (T2DM) and increased cardiovascular risks. Insulin relaxes precapillary arterioles to increase insulin delivery to and action in muscle via recruiting muscle microvasculature and this action is impaired in the insulin resistant states. Metformin is the first line therapy for T2DM and has been shown to improve endothelial function beyond its hypoglycemic effects. Here we aim to examine whether metformin could restore vascular insulin responses in the setting of insulin resistance induced by high fat diet (HFD) feeding via the modulation of endothelial function. Adult, male Sprague-Dawley rats were fed on HFD with or without metformin treatment for 2 weeks. A chow fed group served as control. After dietary intervention, rats were fasted overnight and received a euglycemic-hyperinsulinemic clamp for 120 min. Insulin-mediated muscle microvascular recruitment was assessed before and during insulin infusion using contrast-enhanced ultrasound. Distal saphenous artery was isolated and used for determination of endothelial function and vascular insulin responses. Compared with controls, HFD feeding abolished insulin-induced muscle microvascular recruitment in muscle, decreased insulin-mediated whole body glucose disposal and blunted the vasodilatory response to insulin in small resistance vessel. Metformin treatment significantly enhanced insulin’s microvascular action, effectively rescued small arteriole endothelial function, but did not improve insulin-stimulated whole body glucose disposal in HFD rats. We conclude that metformin could reverse microvascular insulin resistance and attenuate endothelial dysfunction induced by HFD feeding. There findings may provide a novel mechanistic insight into metformin’s cardiovascular protective effect in patients with diabetes. Disclosure J. Liu: None. W. Chai: None. L. Gong: None. K.W. Aylor: None. Z. Liu: None. Funding American Diabetes Association (1-17-ICTS-059 to Z.L.); National Institutes of Health (R01HL094722, R01DK102359)

Role of K+ channels in maintaining the synchrony of spontaneous Ca2+ transients in the mural cells of rat rectal submucosal arterioles.

Mural cells in precapillary arterioles (PCAs) generate spontaneous Ca2+ transients primarily arising from the periodic release of Ca2+ from sarcoendoplasmic reticulum (SR/ER). The Ca2+ release induces Ca2+-activated chloride channel (CaCC)-dependent depolarisations that spread to neighbouring mural cells to develop the synchrony of their Ca2+ transients. Here, we explored the roles of K+ channels in maintaining the synchrony of spontaneous Ca2+ transients. Intracellular Ca2+ dynamics in mural cells were visualised by Cal-520 fluorescence Ca2+ imaging in the submucosal PCAs of rat rectum. Increasing extracellular K+ concentration ([K+]o) from 5.9 to 29.7mM converted synchronous spontaneous Ca2+ transients into asynchronous, high-frequency Ca2+ transients. Similarly, the blockade of inward rectifier K+ (Kir) channels with Ba2+ (50μM) or Kv7 voltage-dependent K+ (Kv7) channels with XE 991 (10μM) disrupted the synchrony of spontaneous Ca2+ transients, while the blockers for large-, intermediate- or small-conductance Ca2+-activated K+ channels had no effect. Kir2.1 immunoreactivity was detected in the arteriolar endothelium but not mural cells. In the PCAs that had been pretreated with XE 991 or Ba2+, nifedipine (1μM) attenuated the asynchronous Ca2+ transients but failed to restore their synchrony. In contrast, levcromakalim, an ATP-sensitive K+ channel opener, restored the synchronous Ca2+ transients. Thus, constitutively active Kv7 and Kir channels appear to be involved in maintaining the relatively hyperpolarised membrane of mural cells. The hyperpolarised membrane prevents depolarisation-induced 'premature' Ca2+ transients to ensure sufficient SR/ER Ca2+ refilling that is required for regenerative Ca2+ release resulting in synchronous Ca2+ transients amongst the mural cells.

Translational research in retinal vascular disease. An approach.

The clinical presentation of the most frequent vision threatening retinal diseases is dominated by lesions indicating that disturbances in retinal blood flow are involved in the pathogenesis of these diseases. The present review describes the experience from a translational strategy pursued to investigate retinal vascular diseases with diabetic retinopathy as the main object. The normal regulation of retinal blood flow is investigated in porcine retinal vessels invitro and exvivo. Subsequently, the invitro findings are translated to clinical studies in normal persons invivo, and it is investigated whether the mechanisms are disturbed in retinal vascular disease. This is followed by clinical intervention studies on these diseases. The approach has been used to investigate pressure autoregulation, metabolic autoregulation and vasomotion in retinal vessels. The investigations have shown that retinal vascular tone can be regulated by receptor-specific agonists and antagonists to vasoactive compounds such as purines, prostaglandins and nitric oxide synthesis and that the vasoactive effects can be modulated by the concentration and the mode of administration of these compounds. Additionally, it has been shown that retinal precapillary arterioles and capillaries not visible by ophthalmoscopy may play an important role for the pathophysiology of retinal vascular disease and its treatment. Future studies should focus on investigating normal and pathological regulation of retinal blood flow in these smaller vessels.

Cardioprotection by spermidine does not depend on structural characteristics of the myocardial microcirculation in aged mice.

Ageing is associated with cardiovascular disease and reduced cardiac function. This cardiac functional decline is accompanied by cardiac remodeling and alterations in cardiomyocyte composition. Recently, it was shown that the natural polyamine spermidine preserves cardiac function and cardiomyocyte composition in old mice. As cardiac function critically relies on blood supply, we tested whether spermidine has also beneficial effects on ageing-associated changes of the myocardial microcirculation. Using transmission electron microscopy, the left ventricular capillaries of young (4-months old) and aged (24-months old) C57BL/6J male mice were investigated by stereology. Aged mice were subdivided into an untreated group and a group that was fed spermidine late in life for 6 months. Specifically, total volume, surface area and length of capillaries as well as endothelial thickness were estimated. Additionally, the total length of precapillary arterioles was assessed. The protein level of VEGF-A was measured using Western blot. Ageing was associated with whole heart and left ventricular hypertrophy. All total capillary-related values (including volume, surface area and length) were significantly higher in 24-month-old mice compared with 4-month-old mice. Moreover, VEGF-A expression was significantly enhanced in aged mice. The mean thickness of the endothelium was not different, but the mean area of myocardium supplied by capillaries was smaller in old mice. Spermidine treatment had no significant effect on the ageing-associated structural changes or VEGF-A expression. In conclusion, in the left ventricles of aged mice the growth of capillaries and arterioles supplying cardiomyocytes were in proportion to whole organ hypertrophy. Spermidine had no effect on quantitative characteristics of capillaries or arterioles, suggesting that the beneficial effects of spermidine on the ageing heart do not depend on the quantitative structural characteristics of the microcirculation which does not exclude potential functional differences between the groups.

Why are pericytes important for brain functions?

Pericytes are mural cells embedded in the basal membrane surrounding endothelial cells in capillary and small vessels (from precapillary arterioles to postcapillary venules). They exist with a high coverage ratio to endothelial cells in the brain and play crucial roles in the formation and maintenance of the blood-brain barrier and the control of blood flow through a close interaction with endothelial cells. Thus, intactness of pericyte is absolutely needed for neuronal/brain functions. Ageing, life-style diseases, hypoperfusion/ischemia, drugs, and genetic factors can primarily cause pericyte dysfunctions, thereby leading to the development or progression of various brain disorders, including cerebrovascular diseases. Because pericytes also play an important role in tissue repair after brain injuries, they have received much attention as a therapeutic target even from the standpoint of functional recovery.

Cochlear Capillary Pericytes.

Capillary pericytes in the cochlea of mammals are-compared to pericytes in other tissues, like the CNS-relatively poorly researched. To begin with, there is still a considerable debate as to whether the very last precapillary arterioles should-due to their contractile properties-may be considered to be pericytes.However, cochlear capillary pericytes have shifted into the center of attention in the past decade. Most mammals show a considerable number of pericytes in the stria vascularis of the cochlea-up to 1300 in a mouse alone. This high number may be explained by the observation that cochlear capillary pericytes may be differentiated into different subgroups, depending on the immune markers that are expressed by them. Corresponding with these subpopulations, cochlear pericytes fulfill three core functions in the physiology of the cochlea: Formation of the intrastrial blood-fluid barrier-Pericytes monitor the ion, fluid, and nutrient household and aid in the homeostasis thereof. Regulation of cochlear blood flow-By contraction on relaxation, pericytes contribute to the regulation of cochlear blood flow, a paramount function parameter of the cochlea. Immune response-Pericytes actually contribute to the immune response in inflammation of the cochlea. Due to these central roles in the physiology of the cochlea, pericytes actually play a major role in numerous cochlear pathologies, including, but not limited to, sudden sensorineural hearing loss, acoustic trauma, and inflammation of the cochlea.

The vasodilating effect of glucose differs among vessels at different branching level in the porcine retina ex vivo

Diabetic retinopathy is characterized by retinal lesions related to disturbances in retinal blood flow. The metabolic dysregulation in diabetes involves hyperglycemia which in both clinical and experimental studies has been shown to induce dilatation of larger retinal vessels, which has been suggested to be mediated by nitric oxide (NO). However, the effects of glucose on the diameter of smaller retinal vessels that are the site of development of diabetic retinopathy are unknown.Diameter changes in porcine retinal arterioles, pre-capillary arterioles and capillaries were studied ex vivo during acute changes in intraluminal glucose concentrations that mimicked changes in plasma glucose in diabetic patients. The experiments were repeated during blocking of NO-synthesis.Intravascular application of 2 mM glucose dilated arterioles and capillaries significantly, while 20 mM glucose dilated precapillary arterioles significantly. Intravascular application of 20 mM glucose dilated precapillary arterioles previously exposed to 2 mM glucose, while no significant diameter changes were observed after application of 2 mM glucose in vessels previously exposed to 20 mM glucose. No diameter changes were observed after application of 5.5 mM glucose in vessels previously exposed to both 2 mM and 20 mM glucose in either order. There was no significant difference between the diameter responses in the absence and presence of NO-synthesis blocker.Glucose induced dilatation of porcine precapillary arterioles ex vivo differs from the response in larger arterioles and capillaries, and the response is unaffected by the blocking of NO-synthesis. This may have implications for understanding the pathophysiology of diseases in the retinal microcirculation, such as diabetic retinopathy.

Retina assessment by optical coherence tomography of diabetic dogs

ABSTRACT: Diabetes mellitus is one of the most common endocrine disorders characterized by relative or absolute lack of insulin; this can lead to several ocular manifestations, among them diabetic retinopathy and cataracts. Diabetic retinopathy (DR) is a microangiopathy that involves retinal precapillary arterioles, postcapillary venules, and large vessels, causing them to be functionally and anatomically incompetent. Hyperglycemia seems to be the most probable cause of damage to the retina due to interference in cellular metabolism and transduction processes. The aim of this study was to evaluate retinal thickness in eight diabetic dogs, four females and four males of different breeds and ages ranging from 6 to 15 years, by optical coherence tomography (OCT) and to compare them with non-diabetic dogs. Assessment provided by OCT in diabetic dogs showed retinal layers thinning and loss of stratification when compared to non-diabetic dogs (198μm versus 219μm respectively), with statistical significance (p=0.008). OCT images may suggest that diabetes mellitus causes retinal neuropathy in dogs, as also seen in diabetic humans.

Three-Dimensional Microscopy Demonstrates Series and Parallel Organization of Human Peripapillary Capillary Plexuses.

To define the three-dimensional topologic organization of the human peripapillary capillary plexuses in order to better understand the hemodynamic characteristics of this retinal circulation. The retinal microvasculature was perfusion labeled in five normal human donor eyes, and optical stacks were collected from regions immediately superior, temporal, inferior, and nasal to the optic disk by using confocal scanning laser microscopy. The spatial location and morphometric characteristics of capillary plexuses were compared. Three-dimensional visualization strategies were used to document the organization of vascular conduits that interconnect capillary beds and to study the communications between capillary beds and precapillary arterioles and postcapillary venules. The peripapillary microcirculation is composed of four capillary plexuses, including the radial peripapillary capillary plexus at the level of the nerve fiber layer, the superficial capillary plexus (SCP) at the level of the ganglion cell layer, the intermediate capillary plexus located at the inner boundary of the inner nuclear layer, and the deep capillary plexus located at the outer boundary of the inner nuclear layer. Capillary diameter and density were significantly different between the four plexuses (both P ≤ 0.011). The SCP is the only capillary bed that receives feeding and draining branches directly from precapillary arterioles and postcapillary venules, respectively. Four different inflow and outflow patterns characterized the communication between the SCP and surrounding capillary beds. The capillary plexuses of the human peripapillary microcirculation are arranged in series and parallel and manifest specializations that likely reflect the unique metabolic demands and biochemical environment of the retinal layers.

Endothelial C-Type Natriuretic Peptide Acts on Pericytes to Regulate Microcirculatory Flow and Blood Pressure

Peripheral vascular resistance has a major impact on arterial blood pressure levels. Endothelial C-type natriuretic peptide (CNP) participates in the local regulation of vascular tone, but the target cells remain controversial. The cGMP-producing guanylyl cyclase-B (GC-B) receptor for CNP is expressed in vascular smooth muscle cells (SMCs). However, whereas endothelial cell-specific CNP knockout mice are hypertensive, mice with deletion of GC-B in vascular SMCs have unaltered blood pressure. We analyzed whether the vasodilating response to CNP changes along the vascular tree, ie, whether the GC-B receptor is expressed in microvascular types of cells. Mice with a floxed GC-B ( Npr2) gene were interbred with Tie2-Cre or PDGF-Rβ-Cre ERT2 lines to develop mice lacking GC-B in endothelial cells or in precapillary arteriolar SMCs and capillary pericytes. Intravital microscopy, invasive and noninvasive hemodynamics, fluorescence energy transfer studies of pericyte cAMP levels in situ, and renal physiology were combined to dissect whether and how CNP/GC-B/cGMP signaling modulates microcirculatory tone and blood pressure. Intravital microscopy studies revealed that the vasodilatatory effect of CNP increases toward small-diameter arterioles and capillaries. CNP consistently did not prevent endothelin-1-induced acute constrictions of proximal arterioles, but fully reversed endothelin effects in precapillary arterioles and capillaries. Here, the GC-B receptor is expressed both in endothelial and mural cells, ie, in pericytes. It is notable that the vasodilatatory effects of CNP were preserved in mice with endothelial GC-B deletion, but abolished in mice lacking GC-B in microcirculatory SMCs and pericytes. CNP, via GC-B/cGMP signaling, modulates 2 signaling cascades in pericytes: it activates cGMP-dependent protein kinase I to phosphorylate downstream targets such as the cytoskeleton-associated vasodilator-activated phosphoprotein, and it inhibits phosphodiesterase 3A, thereby enhancing pericyte cAMP levels. These pathways ultimately prevent endothelin-induced increases of pericyte calcium levels and pericyte contraction. Mice with deletion of GC-B in microcirculatory SMCs and pericytes have elevated peripheral resistance and chronic arterial hypertension without a change in renal function. Our studies indicate that endothelial CNP regulates distal arteriolar and capillary blood flow. CNP-induced GC-B/cGMP signaling in microvascular SMCs and pericytes is essential for the maintenance of normal microvascular resistance and blood pressure.

Dysregulation of miR-135a-5p promotes the development of rat pulmonary arterial hypertension in vivo and in vitro.

Pulmonary arterial hypertension (PAH) is the most common form of pulmonary hypertension. Pulmonary arterial remodeling is closely related to the abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs), which leads to the thickening of the medial layer of muscular arteries and then results in the narrowing or occlusion of the precapillary arterioles and PAH. However, the mechanisms underlying the abnormal proliferation of PASMCs remain unclear. In this study, we established rat primary PAH models using monocrotaline (MCT) injection or hypoxic exposure, then investigated the expression patterns of seven miRNAs associated with multiple pathogenic pathways central to pulmonary hypertension, and further explored the roles and the possible mechanisms of miR-135a during the development of PAH. In the rat primary PAH models, we observed that the expression of miR-135a-5p in lungs was drastically decreased at the initial stage of PAH development after MCT administration or hypoxic exposure, but it increased by 12-fold or 10-fold at the later stage. In vitro study in PASMCs showed a similar pattern of miR-135a-5p expression, with downregulation at 6 h but upregulation at 18, 24, and 48 h after hypoxic exposure. Early, but not late, administration of a miR-135a-5p mimic inhibited hypoxia-induced proliferation of PASMCs. The protective role of early miR-135a-5p agomir in the PAH rat model further supported the hypothesis that the early decrease in the expression of miR-135a-5p contributes to the proliferation of PASMCs and development of PAH, as early administration of miR-135a-5p agomir (10 nM, i.v.) reversed the elevated mean pulmonary arterial pressure and pulmonary vascular remodeling in MCT-treated rats. We revealed that miR-135a-5p directly bound to the 3'-UTR sequence of rat transient receptor potential channel 1 (TRPC1) mRNA and decreased TRPC1 protein expression, thus inhibiting PASMC proliferation. Collectively, our data suggest that dysregulation of miR-135a-5p in PASMCs contributes to the abnormal proliferation of PASMCs and the pathogenesis of PAH. Increasing miR-135a-5p expression at the early stage of PAH is a potential new avenue to prevent PAH development.

Role of capillary pericytes in the integration of spontaneous Ca2+ transients in the suburothelial microvasculature in situ of the mouse bladder.

In the bladder suburothelial microvasculature, pericytes in different microvascular segments develop spontaneous Ca2+ transients with or without associated constrictions. Spontaneous Ca2+ transients in pericytes of all microvascular segments primarily rely on the cycles of Ca2+ uptake and release by the sarco- and endoplasmic reticulum. The synchrony of spontaneous Ca2+ transients in capillary pericytes exclusively relies on the spread of depolarizations resulting from the opening of Ca2+ -activated chloride channels (CaCCs) via gap junctions. CaCC-dependent depolarizations further activate L-type voltage-dependent Ca2+ channels as required for the synchrony of Ca2+ transients in pericytes of pre-capillary arterioles, post-capillary venules and venules. Capillary pericytes may drive spontaneous Ca2+ transients in pericytes within the suburothelial microvascular network by sending CaCC-dependent depolarizations via gap junctions. Mural cells in the microvasculature of visceral organs develop spontaneous Ca2+ transients. However, the mechanisms underlying the integration of these Ca2+ transients within a microvascular unit remain to be clarified. In the present study, the origin of spontaneous Ca2+ transients and their propagation in the bladder suburothelial microvasculature were explored. Cal-520 fluorescence Ca2+ imaging and immunohistochemistry were carried out on mural cells using mice expressing red fluorescent protein (DsRed) under control of the NG2 promotor. NG2(+) pericytes in both pre-capillary arterioles (PCAs) and capillaries developed synchronous spontaneous Ca2+ transients. By contrast, although NG2-DsRed also labelled arteriolar smooth muscle cells, these cells remained quiescent. Both NG2(+) pericytes in post-capillary venules (PCVs) and NG2(-) venular pericytes exhibited propagated Ca2+ transients. L-type voltage-dependent Ca2+ channel (LVDCC) blockade with nifedipine prevented Ca2+ transients or disrupted their synchrony in PCA, PCV and venular pericytes without dis-synchronizing Ca2+ transients in capillary pericytes. Blockade of gap junctions with carbenoxolone or Ca2+ -activated chloride channels (CaCCs) with 4,4'-diisothiocyanato-2,2'-stilbenedisulphonic acid disodium salt prevented Ca2+ transients in PCA and venular pericytes and disrupted the synchrony of Ca2+ transients in capillary and PCV pericytes. Spontaneous Ca2+ transients in pericytes of all microvascular segments were abolished or suppressed by cyclopiazonic acid, caffeine or tetracaine. The synchrony of Ca2+ transients in capillary pericytes arising from spontaneous Ca2+ release from the sarco- and endoplasmic reticulum appears to rely exclusively on CaCC activation, whereas subsequent LVDCC activation is required for the synchrony of Ca2+ transients in pericytes of other microvascular segments. Capillary pericytes may drive spontaneous activity in the suburothelial microvascular unit to facilitate capillary perfusion.

Coronary Blood Flow Is Increased in RV Hypertrophy, but the Shape of Normalized Waves Is Preserved Throughout the Arterial Tree.

A pulsatile hemodynamic analysis was carried out in the right coronary arterial (RCA) tree of control and RV hypertrophy (RVH) hearts. The shape of flow and wall shear stress (WSS) waves was hypothesized to be maintained throughout the RCA tree in RVH (i.e., similar patterns of normalized flow and WSS waves in vessels of various sizes). Consequently, we reconstructed the entire RCA tree down to the first capillary bifurcation of control and RVH hearts based on measured morphometric data. A Womersley-type model was used to compute the flow and WSS waves in the tree. The hemodynamic parameters obtained from experimental measurements were incorporated into the numerical model. Given an increased number of arterioles, the mean and amplitude of flow waves at the inlet of RCA tree in RVH was found to be two times larger than that in control, but no significant differences (p > 0.05) were found in precapillary arterioles. The increase of stiffness in RCA of RVH preserved the shape of normalized flow and WSS waves, but increased the PWV in coronary arteries and reduced the phase angle difference for the waves between the most proximal RCA and the most distal precapillary arteriole. The study is important for understanding pulsatile coronary blood flow in ventricular hypertrophy.

Oral glucose challenge impairs skeletal muscle microvascular blood flow in healthy people.

Skeletal muscle microvascular (capillary) blood flow increases in the postprandial state or during insulin infusion due to dilation of precapillary arterioles to augment glucose disposal. This effect occurs independently of changes in large artery function. However, acute hyperglycemia impairs vascular function, causes insulin to vasoconstrict precapillary arterioles, and causes muscle insulin resistance in vivo. We hypothesized that acute hyperglycemia impairs postprandial muscle microvascular perfusion, without disrupting normal large artery hemodynamics, in healthy humans. Fifteen healthy people (5 F/10 M) underwent an oral glucose challenge (OGC, 50 g glucose) and a mixed-meal challenge (MMC) on two separate occasions (randomized, crossover design). At 1 h, both challenges produced a comparable increase (6-fold) in plasma insulin levels. However, the OGC produced a 1.5-fold higher increase in blood glucose compared with the MMC 1 h postingestion. Forearm muscle microvascular blood volume and flow (contrast-enhanced ultrasound) were increased during the MMC (1.3- and 1.9-fold from baseline, respectively, P < 0.05 for both) but decreased during the OGC (0.7- and 0.6-fold from baseline, respectively, P < 0.05 for both) despite a similar hyperinsulinemia. Both challenges stimulated brachial artery flow (ultrasound) and heart rate to a similar extent, as well as yielding comparable decreases in diastolic blood pressure and total vascular resistance. Systolic blood pressure and aortic stiffness remained unaltered by either challenge. Independently of large artery hemodynamics, hyperglycemia impairs muscle microvascular blood flow, potentially limiting glucose disposal into skeletal muscle. The OGC reduced microvascular blood flow in muscle peripherally and therefore may underestimate the importance of skeletal muscle in postprandial glucose disposal.

MORPHOMETRIC ANALYSIS REMODELING VESSELS HEMOMICROCIRCULATORY BED OF JEJUNUM AT RESECTIONS OF LIVER

Liver resection is widely used in modern surgical departments. Removal of large volumes of the liver leads to postresection portal hypertension, which is complicated by bleeding from varicose veins of the esophagus, stomach, rectum, ascites, splenomegaly with secondary hypersplenism, parenchymal jaundice and portosystemic encephalopathy. The widespread prevalence of this pathology, high mortality from its complications indicates that it is an important medical and social problem. The aim of the study is quantitative morphological study of the features of remodeling the vessels of the hemomicrocirculatory bad of the jejunum at resection of different volumes of the liver. The studies were conducted on 45 sexually mature male rats, which were divided into 3 groups. The first group consisted of 15 intact virtually animals, 2-15 rats after resection of the left lateral part – 31.5% of the parenchyma of the liver, 3-15 animals after resection of the right and left lateral parts of the liver (58.1%). Euthanasia of experimental animals was carried out by bloodletting in conditions of thiopental anesthesia 1 month after the beginning of the experiment. The hemomicrocirculatory bad of the jejunum was studied by injection of its vessels into the carcass-gelatinous mixture, which was injected through the abdominal aorta. From the jejunum, lightened and histologic preparates were prepared and morphometrically studied the vessels of the microhemocirculatory bed. Quantitative indicators were processed statistically, the difference between the comparative values was determined by the Student's criterion. It was established that the severity of structural transformation of the vessels of the microhemocirculatory bad of the jejunum depends on the volume of the removed parenchyma of the liver. The analysis of the obtained results revealed that one month after resection of 31.5% of liver parenchyma, the morphometric parameters of the vessels of the haemomicrocirculatory bad of the jejunum were insignificantly altered. It was determined that resection of 58.1% of liver parenchyma caused postresection portal hypertension and marked remodeling of blood vessels of the hemomicrocirculatory bad of the jejunum, which was characterized by narrowing of arterioles by 23.4%, precapillary arterioles by 22.8%, hemocapillaries by 22.9%%, decrease in the density of microvessels – by 22.4%, the expansion of the capillary venules – by 35.5% and venules – by 28.7%, venous plethora, hypoxia, dystrophy, necrobiosis of cells and tissues, infiltrative processes and sclerosis. Resection of 58.1% of liver parenchyma leads to postresection portal hypertension, pronounced narrowing of lumen of the vessels of the adnexa and exchange units hemomicrocirculatory bed, expansion of the postcapillary venules and venules, venous plethora, hypoxia, dystrophy and necrobiosis of cells and tissues, infiltrative and sclerotic processes in wall of the jejunum.

Impaired retinal microcirculation in patients with Alzheimer's disease.

The goal of this study was to determine the retinal blood flow rate (BFR) and blood flow velocity (BFV) of pre-capillary arterioles and post-capillary venules in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Forty patients (20 AD and 20 MCI) and 21 cognitively normal (CN) controls with a similar age range (± 5 yrs) were recruited. A retinal function imager (RFI) was used to measure BFRs and BFVs of arterioles and venules in the macular region. The thickness of the ganglion cell-inner plexiform layer (GCIPL) was measured using Zeiss Cirrus optical coherence tomography. Macular BFRs in AD group were 2.64 ± 0.20 nl/s (mean ± standard deviation) in arterioles and 2.23 ± 0.19 nl/s in venules, which were significantly lower than in MCI and CN groups (P < 0.05). In addition, BFRs in MCI were lower than in CN in both arterioles and venules (P < 0.05). The BFV of the arterioles was 3.20 ± 1.07 mm/s in AD patients, which was significantly lower than in CN controls (3.91 ± 0.77 mm/s, P = 0.01). The thicknesses of GCIPL in patients with AD and MCI were significantly lower than in CN controls (P < 0.05). Neither BFV nor BFR in arterioles and venules was related to age, GCIPL thickness, mini mental state examination (MMSE) score and disease duration in patients with AD and MCI (P > 0.05). The lower BFR in both arterioles and venules in AD and MCI patients together with the loss of GCIPL were evident, indicating the impairment of the two components in the neurovascular-hemodynamic system, which may play a role in disease progression.

Phylogenetic theory of general pathology. Pericytes, function of the distal arterial bed, metabolic arterial hypertension and hypovolemic shock.

The in vivo roles of pericyte contractile sphincters, smooth muscle cells, endothelial monolayer, precapillary muscle arterioles, exchange and volume capillaries in the physiological balance between peripheral blood pool and the blood pool volume in the distal arterial bed are not fully understood. However, it is highly probable that: 1. There is no primary arterial hypertension. The compensatory biological reaction of arterial pressure (AP) is always secondary, thus indicating the presence of symptomatic or metabolic arterial hypertension (AH). 2. Elevation of AP in proximal arterial bed is a compensatory response to metabolic disorders and impaired microcirculation and metabolism↔microcirculation biological reaction. The response develops locally in the distal arterial bed (muscle arterioles, functional sphincters, pericytes). 3. Metabolic AH is a pathology of the phylogenetically early distal arterial bed , endothelial monolayer, smooth muscle cell and pericyte function. 4. We believe that formation of acute hypovolemic shock is the condition of sphincter (pericyte) atonia in precapillary muscle arterioles with formation of a nonphysiological blood volume in the distal arterial bed when physiological volume of peripheral blood is insufficient to fill the bed. 5. When local disorder in the biological reaction metabolism↔microcirculation is not compensated by endothelium-dependent vasodilation, an efferent innervation signal from the vasomotor center at the entire organism level is sent to the heart and systemic AP increases first in the proximal then in the distal arterial bed. 6. Systemic AP elevation impairs function of the target organs: kidneys, brain and lungs. Each of these organs regulates hydrodynamics in the local pool of extracellular medium, their dysfunction inducing a compensatory response. 7. Metabolic arterial hypertension results from discoordinated systemic compensation of local disorders in the following biological functions: homeostasis, endoecology, trophology and adaptation. This discoordination occurs at the level of paracrine regulated cell communities of functionally different cells which are structural units of each internal organ.

ОСОБЛИВОСТІ РЕМОДЕЛЮВАННЯ СУДИН ГЕМОМІКРОЦИРКУЛЯТОРНОГО РУСЛА КЛУБОВОЇ КИШКИ ПРИ РЕЗЕКЦІЯХ РІЗНИХ ОБ’ЄМІВ ПЕЧІНКИ

Резекцію печінки широко застосовують у сучасних хірургічних відділеннях. Видалення великих об’ємів печінки призводить до пострезекційної портальної гіпертензії, що ускладнюється кровотечами з варикозно розширених вен стравоходу, шлунка, прямої кишки, асцитом, спленомегалією, вторинним гіперспленізмом, паренхіматозною жовтяницею та портосистемною енцефалопатією. Широке розповсюдження даної патології, висока смертність від її ускладнень свідчать, що вона є важливою медичною та соціальною проблемою.Мета дослідження – кількісне морфологічне вивчення особливостей ремоделювання судин гемомікроциркуляторного русла клубової кишки при резекціях різних об’ємів печінки.Матеріали і методи. Дослідження проведено на 43 статевозрілих щурах-самцях, яких поділили на 4 групи: перша група нараховувала 12 інтактних практично здорових тварин, друга – 11 щурів після резекції лівої бокової частки – 31,5 % паренхіми печінки, третя – 12 тварин після резекції лівої бокової і внутрішньої часток – 42,0 % від об’єму печінки, четверта – 8 щурів після резекції правої та лівої бокових часток печінки (58,1 %). Евтаназію дослідних тварин здійснювали кровопусканням в умовах тіопенталового наркозу через місяць від початку експерименту. Гемомікроциркуляторне русло клубової кишки вивчали за допомогою ін’єкції її судин туш-желатиновою сумішшю, яку вводили через черевну аорту. На заморожуючому мікротомі виготовляли зрізи товщиною 30–40 мкм, які зневоднювали в етилових спиртах зростаючої концентрації, просвітлювали у метиленовому ефірі саліцилової кислоти і поміщали в полістирол. З частини спостережень із заповненими судинами туш-желатиновою сумішшю виготовляли гістологічні мікропрепарати, забарвлені гематоксиліном та еозином. Морфометрично визначали діаметри артеріол, передкапілярних артеріол, гемокапілярів, закапілярних венул, венул, щільність судин гемомікроциркуляторного русла на 1 ммl клубової кишки дослідних тварин. Кількісні показники обробляли статистично.Результати досліджень та їх обговорення. Усесторонній аналіз отриманих даних встановив, що резекція 1/3 паренхіми печінки призводила до вираженого ремоделювання судин гемомікроциркуляторного русла клубової кишки, яке характеризувалося вираженим звуженням приносної (артеріол, прекапілярних артеріол), обмінної (гемокапілярів) ланок мікрогемоциркуляторного русла та розширення закапілярних венул і венул, венозного повнокров’я, гіпоксії, дистрофії, некробіозу клітин і тканин. Вираження структурної перебудови судин мікрогемоциркуляторного русла клубової кишки залежить від об’єму видаленої паренхіми печінки. Найбільш вираженим ступінь ремоделювання судин гемомікроциркуляторного русла клубової кишки виявився при резекції 58,1 % паренхіми печінки. Діаметр артеріол при цьому статистично достовірно (р&lt;0,001) зменшився на 31,5 %, передкапілярних артеріол – на 35,4 %, гемокапілярів – на 24,6 %. Закапілярні венули клубової кишки при резекції 58,1 % паренхіми печінки розширилися на 38,9 %, венули – на 31,7 %, щільність мікросудин зменшилася на 28,2 %.Висновки. Резекція 42 % та більше паренхіми печінки призводить до вираженої структурної перебудови судин мікрогемоциркуляторного русла клубової кишки, яке характеризувалося вираженим звуженням приносної (артеріол, прекапілярних артеріол), обмінної (гемокапілярів) ланок мікрогемоциркуляторного русла та розширення закапілярних венул і венул, венозного повнокров’я, гіпоксії, дистрофії, некробіозу клітин і тканин. Вираженість структурної перебудови судин мікрогемоциркуляторного русла клубової кишки залежить від об’єму видаленої паренхіми печінки.

Quantitative imaging mass spectroscopy reveals roles of heme oxygenase-2 for protecting against transhemispheric diaschisis in the brain ischemia.

Carbon monoxide-generating heme oxygenase-2 is expressed in neurons and plays a crucial role for regulating hypoxic vasodilation through mechanisms unlocking carbon monoxide-dependent inhibition of H2S-generating cystathionine β-synthase expressed in astrocytes. This study aims to examine whether heme oxygenase-2 plays a protective role in mice against stroke. Focal ischemia was induced by middle cerebral artery occlusion. Regional differences in metabolites among ipsilateral and contralateral hemispheres were analysed by quantitative imaging mass spectrometry equipped with an image-processing platform to optimize comparison of local metabolite contents among different animals. Under normoxia, blood flow velocity in precapillary arterioles were significantly elevated in heme oxygenase-2-null mice vs controls, while metabolic intermediates of central carbon metabolism and glutamate synthesis were elevated in the brain of heme oxygenase-2-null mice, suggesting greater metabolic demands to induce hyperemia in these mice. In response to focal ischemia, heme oxygenase-2-null mice exhibited greater regions of ischemic core that coincide with notable decreases in energy metabolism in the contralateral hemisphere as well as in penumbra. In conclusion, these findings suggest that heme oxygenase-2 is involved in mechanisms by which not only protects against compromised energy metabolism of the ipsilateral hemisphere but also ameliorates transhemispheric diaschisis of the contralateral hemisphere in ischemic brain.

Assessment of Peritoneal Membrane Arteriolar Structure in Conjunction with Traditional Cardiovascular System Evaluation in Chronic Kidney Disease (CKD) Stage 5 Patients

Background/Aims: Cardiovascular complications are responsible for increased mortality and morbidity in chronic kidney disease (CKD) patients. Functional and structural changes of peritoneal membrane are reported in CKD patients both on conservative treatment and on renal replacement therapy (RRT). The aim of the study was to assess the structure of peritoneal membrane small arteries (precapillary arterioles) in diabetic and non-diabetic CKD stage 5 patients before initiation of peritoneal dialysis (PD) and evaluate its relationship with heart and large arteries abnormalities and with selected biochemical parameters. Methods: Evaluation of 42 CKD stage 5 patients before starting PD. Diabetic (n=26) and non-diabetic (n=16) patients were compared. Peritoneal membrane samples were taken during Tenckhoff catheter insertion. Histopathological evaluation of peritoneal precapillary arterioles (arteriolar evaluation) with measurement of wall thickness (WT) and calculation of lumen/vessel (L/V) ratio was performed in each patients. Echocardiography, intima media thickness (IMT), pulse wave velocity (PWV), ambulatory blood pressure monitoring (ABPM) and biochemical parameters assessment: serum albumin (SA), total cholesterol (TCH), hemoglobin (Hgb), parathormone (PTH), serum calcium (Ca), serum phosphorus (P), transferrin saturation (TSAT%), C-reactive protein (CRP) were performed in each participant. Results: There were no statistically significant differences in peritoneal membrane arteriolar indices – wall thickness (WT) and L/V ratio between investigated groups. There was statistically significant higher PWV value in diabetic patients. There were no statistically significant differences in echocardiographic indices, IMT, laboratory data in analyzed groups. There were some linear correlations between: PWV vs IMT (R=0,84; p=0,0006); PWV vs PP (R=0,58; p=0,03) in non-diabetic and linear correlation between: PWV vs age (R=0,75; p=0,02); WT vs DP (R=-0,93; p=0,001); WT vs DBP ( R=0,64; p=0,04) in diabetic group. Conclusion: Peritoneal membrane arteriolar damage seems to be an integrated part of cardiovascular system damage in CKD stage 5 patients.