Control Of Local Blood Flow Research Articles

Reduced microvascular flow-mediated dilation in Syrian hamsters lacking d-sarcoglycan is caused by increased oxidative stress.

d-sarcoglycan mutation reduces mechanotransduction and induces dilated cardiomyopathy with aging. We hypothesized that in young hamsters with d-sarcoglycan mutation, which do not show cardiomyopathy, flow mechanotransduction might be affected in resistance arteries as the control of local blood flow. Flow-mediated-dilation (FMD) was measured in isolated mesenteric resistance arteries, using 3-months old hamsters carrying a mutation in the d-sarcoglycan gene (CH-147) and their control littermates. The FMD was significantly reduced in the CHF-147 group. Nevertheless, passive arterial diameter, vascular structure and endothelium-independent dilation to sodium nitroprusside were not modified. Contraction induced by KCl was not modified, whereas contraction due to phenylephrine was increased. The basal NO production and total eNOS expression levels were not altered. Nevertheless, eNOS phosphorylation, FAKs and RhoA expression were reduced in CH-147. In contrast, p47phox, COX2, iNOS and reactive oxygen species levels were higher in the endothelium of CHF-147 hamsters. Reducing ROS levels using the superoxide dismutase analog Tempol significantly restored the flow-mediated dilation (FMD) levels in CHF-147 hamsters. However, treatment with the COX-2 inhibitor NS-398 showed a non-significant improvement in FMD.

The relevance of vascular adjustments to hemodynamic control in the face of temperature change in Crotalus durissus.

The presence of cardiac shunts in ectothermic tetrapods is thought to be consistent with active vascular modulations for proper hemodynamic support. Local control of blood flow modulates tissue perfusion and thus systemic conductance (Gsys) is assumed to increase with body temperature (Tb) to accommodate higher aerobic demand. However, the general increase of Gsys presses for a higher right-to-left (R-L) shunt, which reduces arterial oxygen concentration. In contrast, Tb reduction leads to a Gsys decrease and a left-to-right shunt, which purportedly increases pulmonary perfusion and plasma filtration in the respiratory area. This investigation addressed the role of compensatory vascular adjustments in the face of the metabolic alterations caused by Tb change in the South American rattlesnake (Crotalus durissus). Cardiovascular recordings were performed in decerebrated rattlesnake preparations at 10, 20 and 30°C. The rise in Tb increased metabolic demand, and correlated with an augmentation in heart rate. Although cardiac output increased, systemic stroke volume reduced while pulmonary stroke volume remained stable. Although that resulted in a proportionally higher increase in pulmonary blood flow, the R-L shunt was maintained. While the systemic compliance of large arteries was the most relevant factor in regulating arterial systemic blood pressure, peripheral conductance of pulmonary circulation was the major factor influencing the final cardiac shunt. Such dynamic adjustment of systemic compliance and pulmonary resistance for shunt modulation has not been demonstrated before and contrasts with previous knowledge on shunt control.

Elevated sympathetic-mediated vasoconstriction at rest but intact functional sympatholysis during exercise in heart failure with reduced ejection fraction.

Patients with heart failure with reduced ejection fraction (HFrEF) have exaggerated sympathoexcitation and impaired peripheral vascular conductance. Evidence demonstrating consequent impaired functional sympatholysis is limited in HFrEF. This study aimed to determine the magnitude of reduced limb vascular conductance during sympathoexcitation and whether functional sympatholysis would abolish such reductions in HFrEF. Twenty patients with HFrEF and 22 age-matched controls performed the cold pressor test (CPT) [left foot 2-min in -0.5 (1)°C water] alone and with right handgrip exercise (EX + CPT). Right forearm vascular conductance (FVC), forearm blood flow (FBF), and mean arterial pressure (MAP) were measured. Patients with HFrEF had greater decreases in %ΔFVC and %ΔFBF during CPT (both P < 0.0001) but not EX + CPT (P = 0.449, P = 0.199) compared with controls, respectively. %ΔFVC and %ΔFBF decreased from CPT to EX + CPT in patients with HFrEF (both P < 0.0001) and controls (P = 0.018, P = 0.015), respectively. MAP increased during CPT and EX + CPT in both groups (all P < 0.0001). MAP was greater in controls than in patients with HFrEF during EX + CPT (P = 0.025) but not CPT (P = 0.209). In conclusion, acute sympathoexcitation caused exaggerated peripheral vasoconstriction and reduced peripheral blood flow in patients with HFrEF. Handgrip exercise abolished sympathoexcitatory-mediated peripheral vasoconstriction and normalized peripheral blood flow in patients with HFrEF. These novel data reveal intact functional sympatholysis in the upper limb and suggest that exercise-mediated, local control of blood flow is preserved when cardiac limitations that are cardinal to HFrEF are evaded with dynamic handgrip exercise.NEW & NOTEWORTHY Patients with HFrEF demonstrate impaired peripheral blood flow regulation, evidenced by heightened peripheral vasoconstriction that reduces limb blood flow in response to physiological sympathoexcitation (cold pressor test). Despite evidence of exaggerated sympathetic vasoconstriction, patients with HFrEF demonstrate a normal hyperemic response to moderate-intensity handgrip exercise. Most importantly, acute, simultaneous handgrip exercise restores normal limb vasomotor control and vascular conductance during acute sympathoexcitation (cold pressor test), suggesting intact functional sympatholysis in patients with HFrEF.

Does the Prolonged Duration of Continuous Ambulatory Peritoneal Dialysis Affect the Serum Levels of Endothelin-1 and Nitric Oxide?

End-stage renal disease and its treatment with continuous ambulatory peritoneal dialysis (CAPD) can affect almost all organs and organ systems including vascular endothelium. Consequently, disturbance in the production of vasoactive substances endothelin-1 (ET-1) and nitric oxide (NO) occurs in these patients. There are only a small number of studies that investigated the impact of long-term CAPD on imbalance in production of vasoactive substances ET-1 and NO among these patients. Therefore, our study aimed to investigate the impact of duration of CAPD on potential overproduction of ET-1 and NO in uremic patients. This study included 23 uremic patients [10 males, mean age: 56.3 (±16.2) years] treated with CAPD. All studied patients were further divided into subgroups, groups A and B. Group A included patients on treatment with CAPD <5 years, and group B included those on treatment longer than five years. Our results showed that serum levels of these vasoactive substances are significantly higher among patients treated with CAPD longer than five years (ET-1: 51.24 ± 32.11 vs. 139.53 ± 42.42; NO: 15.50 ± 2.57 vs. 26.57 ± 5.96, respectively). We concluded that imbalance in production of vasoactive substances is present in long-term CAPD treatment and this imbalance can lead to disturbance in the local blood flow control.

Convergence of Eastern and Western Medicine

The article argues that, thanks to the study of the nature of meridional connections, it is possible to open the mechanism of interaction of body systems through the control of local blood flow and introduce methods of diagnosis and treatment, providing local blood supply through the control of heart rate variability (HRV).

A theoretical model for flow regulation in the cerebral cortex: role of penetrating arterioles

Activation of a region of the brain results in a local increase in blood flow, a process known as neurovascular coupling (NVC). Here, a theoretical model of blood flow regulation in the cerebral cortex is utilized to investigate the potential role of penetrating arterioles as the primary mechanism for local control of blood flow. Penetrating arterioles connect pial arterioles with the capillary meshwork deeper in the cortex and have a typical length of approximately 600 μm. This is about one‐sixth of the length of corresponding small arterioles in skeletal muscle. The question arises whether these relatively short arterioles can achieve the range of flow modulation observed in the cerebral cortex. A previously developed compartmental model for flow regulation in skeletal muscle was modified to represent the structure of cerebral microvasculature. A compartment consisting of penetrating arterioles with a reference diameter of 14.8 μm and a length of 600 μm is assumed to provide active control of blood flow. Smooth muscle tone in these arterioles is assumed to depend on a combination of signals representing myogenic, shear‐dependent, and metabolic responses. The metabolic response is represented by a change in endothelial cell membrane potential, propagated upstream along arterioles by conducted responses. Sensitivity of diameter to membrane potential was determined based on experimental data. According to the model, a hyperpolarization of 40 mV can result in an increase in local blood flow by approximately 70%. Since increases in local blood flow of 50% with activation have been observed, these results imply that vasoconstriction and vasodilation by penetrating arterioles can provide typical levels of blood flow control seen in neurovascular coupling.

Comparative and Evolutionary Aspects of the Digestive System and Its Enteric Nervous System Control.

All life forms must gain nutrients from the environment and from single cell organisms to mammals a digestive system is present. Components of the digestive system that are recognized in mammals can be seen in the sea squirt that has had its current form for around 500my. Nevertheless, in mammals, the organ system that is most varied is the digestive system, its architecture being related to the dietary niche of each species. Forms include those of foregut or hindgut fermenters, single or multicompartment stomachs and short or capacious large intestines. Dietary niches include nectarivores, folivores, carnivores, etc. The human is exceptional in that, through food preparation (>80% of human consumption is prepared food in modern societies), humans can utilize a wider range of foods than other species. They are cucinivores, food preparers. In direct descendants of simple organisms, such as sponges, there is no ENS, but as the digestive tract becomes more complex, it requires integrated control of the movement and assimilation of its content. This is achieved by the nervous system, notably the enteric nervous system (ENS) and an array of gut hormones. An ENS is first observed in the phylum cnidaria, exemplified by hydra. But hydra has no collections of neurons that could in any way be regarded as a central nervous system. All animals more complex than hydra have an ENS, but not all have a CNS. In mammals, the ENS is extensive and is necessary for control of movement, enteric secretions and local blood flow, and regulation of the gut immune system. In animals with a CNS, the ENS and CNS have reciprocal connections. From hydra to human, an ENS is essential to life.

Morphological changes of the myenteric plexus at different gut segments of human fetuses

ABSTRACT The neural crest cell-derived enteric nervous system (ENS) is the intrinsic innervation of the gastrointestinal tract (GIT) which consists of neurons and enteric glia cells in the myenteric ganglia and forming plexus. The ENS consists mainly of submucosal and myenteric plexuses. It has various functions on the GIT, which include control of local blood flow, motility, mucosal transport, secretions, immune modulation as well as endocrine functions and coordinated contractile activity of smooth muscle. The knowledge on the development of the innervations at different segments of the gut in humans from 11 to 26 weeks of gestation (WG) may help in understanding the pathophysiology of various congenital diseases affecting the ENS. The aim of this study is to determine the morphology of the myenteric plexus in the esophagus, ascending colon and sigmoid colon at various weeks of gestation. Tissue samples from 10 naturally terminated fetuses aged 11–26 WG were processed for hematoxylin and eosin staining and immunohistochemistry assay. The neurons, enteric glia, the smooth muscle were visualized using PGP9.5, Vimentin and S-100 antibodies. The number of neurons and enteric glial cells appeared lowest in the esophagus than the ascending and sigmoid colon. The myenteric ganglion was closely apposed to each other, forming a continuous arch along the entire circumference of gut sections of ascending and sigmoid colon but the myenteric ganglia in the esophagus was thinly populated and widely spread in the fetus at 13 WG. As the fetal gastrointestinal tract grew in diameter and length, the myenteric ganglia became discernible.

Evidence for improved systemic and local vascular function after long-term passive static stretching training of the musculoskeletal system.

Vascular function and arterial stiffness are important markers of cardiovascular health and cardiovascular co-morbidity. Transitional phases of hypoemia and hypermia, with consequent fluctuations in shear rate, occuring during repetitive passive stretching adminstration (passive stretching training) may constitute an effective stimulus to induce an amelioration in vascular function, arterial stiffness and vascular remodelling by improving central and local blood flow control mechanisms. Vascular function, arterial stiffness and vascular remodelling were evaluated before and after 12weeks of passive stretching training and after 6weeks from training cessation, in the femoral, popliteal (treated with stretching), and brachial arteries (untreated) of both sides. After passive stretching training, vascular function and arterial remodelling improved, and arterial stiffness decreased in all the arteries, suggesting modifications of both central and local blood flow control mechanisms. Passive stretching-induced improvements related to central mechanisms seemed to have a short duration, as they returned to pre-training baseline within 6weeks from training cessation, whereas those more related to a local mechanism persisted in the follow-up. Acute passive stretching (PS) effects on blood flow ( ), shear rate ( ), and vascular function in the feeding arteries of the stretched muscle have been extensively investigated; however, few data are available on vascular adjustments induced by long-term PS training. We investigated the effects of PS training on vascular function and stiffness of the involved (femoral and popliteal) and uninvolved (brachial) arteries. Our hypothesis was that PS-induced changes in and would improve central and local mechanisms of control. Thirty-nine participants were randomly assigned to bilateral PS (n=14), monolateral PS (n=13) or no PS training (n=12). Vascular function was measured before and after 12weeks of knee extensor and plantar flexor muscles' PS training by single passive limb movement and flow-mediated dilatation (FMD). Central (carotid-femoral artery PWV, PWVCF ) and peripheral (carotid-radial artery PWV, PWVCR ) arterial stiffness was measured by pulse-wave velocity (PWV), together with systolic (SBP) and diastolic (DBP) blood pressure. After PS training, increases of 30%, 25% and 8% (P<0.05) in femoral Δ , popliteal and brachial artery FMD%, respectively, occurred in both PS training groups. A decrease in PWVCF , PWVCR , SBP and DBP (-25%, -17%, -4% and -8%, respectively; P<0.05) was noted. No changes occurred in controls. Vascular function improved and arterial stiffness reduced in the arteries involved and uninvolved with PS training, suggesting modifications in both central and local control mechanisms. PS-induced improvements had a short duration in some of vascular function parameters, as they returned to baseline within 6weeks of PS training cessation.

Blood Flow Control of the Microcirculation by KATP Channels in Ventricular Myocytes

The metabolic demands of the working myocardium underlies the control of blood flow to the cardiac myocytes. However, little is known about the details of the signals that are generated by metabolic need and how these signals are linked into a rapid‐response negative feedback control of blood flow. Here, using the state‐of‐the‐art confocal microscopy and whole mount immunostaining techniques and other fluorescent labels, we have investigated both the anatomic organization of the vasculature and the control mechanisms of blood flow. Our results show the key cellular elements of the system are connected to each other electrically by means of gap junctions (Connexin 43). They connect ventricular myocytes to capillary endothelial cells which are connected to pericytes and the small artery endothelium. Gap junctions thus allow the time‐averaged hyperpolarization of ventricular myocytes (due to the opening of ATP‐sensitive K+ channels (KATP) following metabolic need) to produce hyperpolarization in the rest of the system. By this means relaxation of the pericytes and the smooth muscle cells could produce an increase in blood flow with O2 and nutrition to the ventricular myocytes. Initial results showing this physiological feedback control system that appear to manage blood flow control in heart were tested in a perfused mouse cardiac papillary muscle preparation. The functional changes of arterioles and capillaries in the ex vivo heart were monitored using high‐speed confocal microscopes that include a combination of XY (Nipkow disk) and point‐scanner confocals. Our results suggest that KATP opener pinacidil caused perfusion pressure decrease (blood flow increase) while KATP blocker glibenclamide causes perfusion pressure increase in paced or quiescent heart, indicating the functional involvement of KATP channels in local blood flow control. Pinacidil‐induced perfusion pressure reduction does not differ on smooth muscle specific Kir6.1 mutated mice, suggesting the least role of smooth muscle KATP in the local blood flow regulation. An additional contribution to blood flow elevation may be attributed to extracellular K+ ([K+]o) increases (from ventricular myocyte KATP and other K+ channels), which leads to the hyperpolarization of capillary endothelial cells through the activation of inward rectifier K+ channels (Kir). Thus, the activation of KATP in cardiomyocytes caused by metabolic increase links to the local increase in blood flow. Taken together, these data provide compelling evidence that blood flow control in the mammalian heart is a classic negative‐feedback signaling mechanism that links the metabolism of ventricular myocytes to locally increased blood flow through an electrically controlled signaling system.

ATP- and voltage-dependent electro-metabolic signaling regulates blood flow in heart

Local control of blood flow in the heart is important yet poorly understood. Here we show that ATP-sensitive K+ channels (KATP), hugely abundant in cardiac ventricular myocytes, sense the local myocyte metabolic state and communicate a negative feedback signal-correction upstream electrically. This electro-metabolic voltage signal is transmitted instantaneously to cellular elements in the neighboring microvascular network through gap junctions, where it regulates contractile pericytes and smooth muscle cells and thus blood flow. As myocyte ATP is consumed in excess of production, [ATP]i decreases to increase the openings of KATP channels, which biases the electrically active myocytes in the hyperpolarization (negative) direction. This change leads to relative hyperpolarization of the electrically connected cells that include capillary endothelial cells, pericytes, and vascular smooth muscle cells. Such hyperpolarization decreases pericyte and vascular smooth muscle [Ca2+]i levels, thereby relaxing the contractile cells to increase local blood flow and delivery of nutrients to the local cardiac myocytes and to augment ATP production by their mitochondria. Our findings demonstrate the pivotal roles of local cardiac myocyte metabolism and KATP channels and the minor role of inward rectifier K+ (Kir2.1) channels in regulating blood flow in the heart. These findings establish a conceptually new framework for understanding the hugely reliable and incredibly robust local electro-metabolic microvascular regulation of blood flow in heart.

Using lectures to identify student misconceptions: a study on the paradoxical effects of hyperkalemia on vascular smooth muscle.

Medical students have difficulty understanding the mechanisms underlying hyperkalemia-mediated local control of blood flow. Such control mechanisms are crucial in the brain, kidney, and skeletal muscle vasculature. We aimed to identify medical students' misconceptions via assessment of students' in-class knowledge and, subsequently, improve future teaching of this concept. In-class polling was performed with the TurningPoint clicker response system (n = 860) to gauge students' understanding of three physiological concepts related to hyperkalemia: membrane potential (Vm), conductance, and smooth muscle response. Vm includes the concepts of equilibrium potential (Veq) for specific ions, as well as driving force (DF = Vm - Veq). Students understood the concept of DF (~70% answered correctly), suggesting their understanding of Vm. However, students misunderstood that hyperkalemia results in depolarization (~52% answered correctly) and leads to an increase in potassium conductance (~31% answered correctly). Clarification of the type of smooth muscle as vascular increased the percentage of correct responses (~51 to 73%). The data indicate that students lacked knowledge of specific potassium conductance in various muscle types, resulting in divergent responses, such as the canonical depolarization in skeletal muscle versus hyperpolarization in smooth muscle cells during hyperkalemia. Misunderstanding of this crucial concept of conductance is directly related to the students' performance. Furthermore, we connected the paradoxical effect of hyperkalemia to pathological acute and chronic hyperkalemia clinical scenarios.

Presence and expression of apelin and apelin receptor in bitch placenta

Apelin is a potent inotropic agent causing endothelium-mediated vasodilation and is involved in vessel formation by interacting with a specific receptor. Its cardiovascular profile suggests a role in the regulation of gestational hemodynamic changes. The expression of apelin and its receptor has been reported in some portions of the reproductive tract of different mammalian species. As far as we know, there are no reports describing the expression of apelin and apelin receptor in bitch’s placenta. Therefore, the aim of this study was to investigate, for the first time, the presence and distribution of apelin and apelin receptor in bitch placenta by molecular biology and immunohistochemical techniques. Sixteen adult female half-breed bitches were used. The animals were divided into two groups based on the stage of pregnancy: group 1 (mid-gestation n = 8) and group 2 (end gestation n = 8). These bitches were subjected to ovariohysterectomy (group1) or non-conservative caesarean section (group 2). The immunohistochemical technique revealed the presence of positive immune reaction for apelin and apelin receptor in all the samples examined at 30 days and at the end of pregnancy. In particular, apelin and apelin receptor staining was evident in the cytoplasms of cytotrophoblasts and in epithelial cells of the maternal portion. Even if not included into the structure of the placenta, the uterine glands also exhibited a positive immune reaction for apelin and apelin receptor. The RT-PCR analysis showed the presence of transcripts for apelin and apelin receptor in all the placenta samples examined. On the basis of our results it was also possible to hypothesize a potential role of apelin in the control of local placenta blood flow during pregnancy development in bitches.

Disentangling the Gordian knot of local metabolic control of coronary blood flow.

Recognition that coronary blood flow is tightly coupled with myocardial metabolism has been appreciated for well over half a century. However, exactly how coronary microvascular resistance is tightly coupled with myocardial oxygen consumption (MV̇o2) remains one of the most highly contested mysteries of the coronary circulation to this day. Understanding the mechanisms responsible for local metabolic control of coronary blood flow has been confounded by continued debate regarding both anticipated experimental outcomes and data interpretation. For a number of years, coronary venous Po2 has been generally accepted as a measure of myocardial tissue oxygenation and thus the classically proposed error signal for the generation of vasodilator metabolites in the heart. However, interpretation of changes in coronary venous Po2 relative to MV̇o2 are quite nuanced, inherently circular in nature, and subject to confounding influences that remain largely unaccounted for. The purpose of this review is to highlight difficulties in interpreting the complex interrelationship between key coronary outcome variables and the arguments that emerge from prior studies performed during exercise, hemodilution, hypoxemia, and alterations in perfusion pressure. Furthermore, potential paths forward are proposed to help to facilitate further dialogue and study to ultimately unravel what has become the Gordian knot of the coronary circulation.

Effect of local skin blood flow during light and medium activities on local skin temperature predictions

The quality of local skin temperature prediction by thermophysiological models depends on the local skin blood flow (SBF) control functions. These equations were derived for low activity levels (0.8-1met) and mostly in sitting or supine position. This study validates and discusses the prediction of foot SBF during activities of 1-3met in male and females, and the effect on the foot skin temperature prediction (ΔTskin,foot) using the thermophysiological simulation model ThermoSEM. The SBF at the foot was measured for ten male and ten female human subjects at baseline and during three activities (sitting, walking at 1km/h, preferred walking around 3km/h). Additional measurements included the energy expenditure, local skin temperatures (Tskin,loc), environmental conditions and body composition. Measured, normalized foot SBF is 2-8 times higher than the simulated SBF during walking sessions. Also, SBF increases are significantly higher in females vs. males (preferred walking: 4.8±1.5 versus 2.7±1.4, P < 0.05). The quality of ΔTskin,foot using the simulated foot SBF is poor (median deviation is -4.8°C, maximumumdeviationis-6°C). Using the measured SBF in ThermoSEM results in an improved local skin temperature prediction (new maximum deviation is -3.3°C). From these data a new SBF model was developed that includes the walking activity level and gender, and improves SBF prediction and ΔTskin,foot of the thermophysiological model. Accurate SBF and local skin temperature predictions are beneficial in optimizing thermal comfort simulations in the built environment, and might also be applied in sport science or patient's temperature management.

Retinal capillary perfusion: Spatial and temporal heterogeneity.

The central role of the cardiovascular system is to maintain adequate capillary perfusion. The spatially and temporally heterogeneous nature of capillary perfusion has been reported in some organs. However, such heterogeneous perfusion properties have not been sufficiently explored in the retina. Arguably, spatial and temporal heterogeneity of capillary perfusion could be more predominant in the retina than that in other organs. This is because the retina is one of the highest metabolic demand neural tissues yet it has a limited blood supply due to optical requirements. In addition, the unique heterogeneous distribution of retinal neural cells within different layers and regions, and the significant heterogeneity of intraretinal oxygen distribution and consumption add to the complexity. Retinal blood flow distribution must match consumption of nutrients such as oxygen and glucose within the retina at the cellular level in order to effectively maintain cell survival and function. Sophisticated local blood flow control in the microcirculation is likely required to control the retinal capillary perfusion to supply local retinal tissue and accommodate temporal and spatial variations in metabolic supply and demand. The authors would like to update the knowledge of the retinal microvessel and capillary network and retinal oxidative metabolism from their own studies and the work of others. The coupling between blood supply and energy demands in the retina is particularly interesting. We will mostly describe information regarding the retinal microvessel network and retinal oxidative metabolism relevant to the spatial and temporal heterogeneity of capillary perfusion. We believe that there is significant and necessary spatial and temporal heterogeneity and active regulation of retinal blood flow in the retina, particularly in the macular region. Recently, retinal optical coherence tomography angiography (OCTA) has been widely used in ophthalmology, both experimentally and clinically. OCTA could be a valuable tool for examining retinal microvessel and capillary network structurally and has potential for determining retinal capillary perfusion and its control. We have demonstrated spatial and temporal heterogeneity of capillary perfusion in the retina both experimentally and clinically. We have also found close relationships between the smallest arterioles and capillaries within paired arterioles and venules and determined the distribution of smooth muscle cell contraction proteins in these vessels. Spatial and temporal heterogeneity of retinal capillary perfusion could be a useful parameter to determine retinal microvessel regulatory capability as an early assay for retinal vascular diseases. This topic will be of great interest, not only for the eye but also other organs. The retina could be the best model for such investigations. Unlike cerebral vessels, retinal vessels can be seen even at the capillary level. The purpose of this manuscript is to share our current understanding with the readers and encourage more researchers and clinicians to investigate this field. We begin by reviewing the general principles of microcirculation properties and the spatial and temporal heterogeneity of the capillary perfusion in other organs, before considering the special requirements of the retina. The local heterogeneity of oxygen supply and demand in the retina and the need to have a limited and well-regulated retinal circulation to preserve the transparency of the retina is discussed. We then consider how such a delicate balance of metabolic supply and consumption is achieved. Finally we discuss how new imaging methodologies such as optical coherence tomography angiography may be able to detect the presence of spatial and temporal heterogeneity of capillary perfusion in a clinical setting. We also provide some new information of the control role of very small arterioles in the modulation of retinal capillary perfusion which could be an interesting topic for further investigation.

Caffeine and Reactive Hyperemia

The physiological/pathophysiological effects of caffeine on the human cardiovascular system have not been investigated by physiologists and are poorly understood. In a world where caffeinated beverages are evidently the adult’s drug of choice (coffee, energy drinks, soda, tea) investigating their effects on the physiology of the cardiovascular system is of considerable importance. In this experiment, we investigated caffeine, taken orally as a tablet, on reactive hyperemia, a form of local control of blood flow. Young adults between the ages of 18 and 21 years were the experimental subjects. They were instrumented to monitor systemic arterial blood pressure, peripheral blood flow, calculated peripheral vascular resistance, heart rate and an electrocardiogram during a reactive hyperemia maneuver in the absence and presence of caffeine. Caffeine-mediated peripheral vasoconstriction was observed as early as 15 minutes after its consumption. Forty-five minutes later (60 min after consumption of caffeine) peripheral vasoconstriction was so prominent that reactive hyperemia was abolished. This was reflected, in part, as a marked and significant reduction in post-ischemia reactive hyperemia that accompanied a 2.5-fold increase in peripheral vascular resistance (P 0.05). Heart rate was unaffected by caffeine under our experimental conditions. We conclude that caffeine has the ability to inhibit important cardiovascular properties, including reactive hyperemia. If the effects that were seen in a digit are indicative of what caffeine might do in the heart and/or brain, then one has to question the wisdom of regularly consuming caffeine. More experimental physiological and pharmacological investigation is needed.

Active role of capillary pericytes during stimulation-induced activity and spreading depolarization.

Spreading depolarization is assumed to be the mechanism of migraine with aura, which is accompanied by an initial predominant hyperaemic response followed by persistent vasoconstriction. Cerebral blood flow responses are impaired in patients and in experimental animals after spreading depolarization. Understanding the regulation of cortical blood vessels during and after spreading depolarization could help patients with migraine attacks, but our knowledge of these vascular mechanisms is still incomplete. Recent findings show that control of cerebral blood flow does not only occur at the arteriole level but also at capillaries. Pericytes are vascular mural cells that can constrict or relax around capillaries, mediating local cerebral blood flow control. They participate in the constriction observed during brain ischaemia and might be involved the disruption of the microcirculation during spreading depolarization. To further understand the regulation of cerebral blood flow in spreading depolarization, we examined penetrating arterioles and capillaries with respect to vascular branching order, pericyte location and pericyte calcium responses during somatosensory stimulation and spreading depolarization. Mice expressing a red fluorescent indicator and intravenous injections of FITC-dextran were used to visualize pericytes and vessels, respectively, under two-photon microscopy. By engineering a genetically encoded calcium indicator we could record calcium changes in both pericytes around capillaries and vascular smooth muscle cells around arterioles. We show that somatosensory stimulation evoked a decrease in cytosolic calcium in pericytes located on dilating capillaries, up to the second order capillaries. Furthermore, we show that prolonged vasoconstriction following spreading depolarization is strongest in first order capillaries, with a persistent increase in pericyte calcium. We suggest that the persistence of the 'spreading cortical oligaemia' in migraine could be caused by this constriction of cortical capillaries. After spreading depolarization, somatosensory stimulation no longer evoked changes in capillary diameter and pericyte calcium. Thus, calcium changes in pericytes located on first order capillaries may be a key determinant in local blood flow control and a novel vascular mechanism in migraine. We suggest that prevention or treatment of capillary constriction in migraine with aura, which is an independent risk factor for stroke, may be clinically useful.

Regulation of mitochondrial dynamics in astrocytes: Mechanisms, consequences, and unknowns.

Astrocytes are the major glial cell in the central nervous system. These polarized cells possess numerous processes that ensheath the vasculature and contact synapses. Astrocytes play important roles in synaptic signaling, neurotransmitter synthesis and recycling, control of nutrient uptake, and control of local blood flow. Many of these processes depend on local metabolism and/or energy utilization. While astrocytes respond to increases in neuronal activity and metabolic demand by upregulating glycolysis and glycogenolysis, astrocytes also possess significant capacity for oxidative (mitochondrial) metabolism. Mitochondria mediate energy supply and metabolism, cellular survival, ionic homeostasis, and proliferation. These organelles are dynamic structures undergoing extensive fission and fusion, directed movement along cytoskeletal tracts, and degradation. While many of the mechanisms underlying the dynamics of these organelles and their physiologic roles have been characterized in neurons and other cells, the roles that mitochondrial dynamics play in glial physiology is less well understood. Recent work from several laboratories has demonstrated that mitochondria are present within the fine processes of astrocytes, that their movement is regulated, and that they contribute to local Ca2+ signaling within the astrocyte. They likely play a role in local ATP production and metabolism, particularly that of glutamate. Here we will review these and other findings describing the mechanism by which mitochondrial dynamics are regulated in astrocytes, how mitochondrial dynamics might influence astrocyte and brain metabolism, and draw parallels to mitochondrial dynamics in neurons. Additionally, we present new analyses of the size, distribution, and dynamics of mitochondria in astrocytes performed using in vivo using 2-photon microscopy.

Disruption of TRPV3 Impairs Heat-Evoked Vasodilation and Thermoregulation: A Critical Role of CGRP

Sensing environmental temperature is a key factor allowing individuals to maintain thermal homeostasis via thermoregulatory mechanisms, including changes to skin blood flow. Among transient receptor potential channels, transient receptor potential vanilloid 3 (TRPV3) is a heat-activated cation channel highly expressed in keratinocytes. However, the role of TRPV3 in triggering heat-evoked cutaneous vasodilation is unknown. Using a murine invivo model of local acute environmental heat exposure in the skin, we show that TRPV3 is involved in the local thermoregulatory control of skin blood flow by initiating the release of calcitonin gene-related peptide and nitric oxide in response to local heating of the skin. In addition to their contribution in local heat-evoked vasodilation, TRPV3, calcitonin gene-related peptide, and nitric oxide also contribute to internal body temperature stability during passive whole-body heating. This study provides invivo demonstration of the role of TRPV3 as a strong modulator of cutaneous vascular thermoregulatory mechanisms.