Adaptation of the Cerebrocortical Circulation to Carotid Artery Occlusion Involves Blood Flow Redistribution between Cortical Regions and is Independent of eNOS

Cerebral circulation is secured by feed-forward and feed-back control pathways to maintain and eventually reestablish the optimal oxygen and nutrient supply of neurons in case of disturbances of the cardiovascular system. Using the high temporal and spatial resolution of laser-speckle imaging we aimed to analyze the pattern of cerebrocortical blood flow (CoBF) changes after unilateral (left) carotid artery occlusion (CAO) in anesthetized mice in order to evaluate the contribution of macrovascular (Willis circle) vs. pial collateral vessels as well as that of endothelial nitric oxide synthase (eNOS) to the cerebrovascular adaptation to CAO. In wild-type mice CoBF reduction in the left temporal cortex started immediately after CAO, reaching its maximum (-26%) at 5-10 s. Thereafter, CoBF recovered close to the pre-occlusion level within 30 s indicating the activation of feed-back pathway(s). Interestingly, the frontoparietal cerebrocortical regions also showed CoBF reduction in the left (-17-19%) but not in the right hemisphere, although these brain areas receive their blood supply from the common azygos anterior cerebral artery in mice. In eNOS-deficient animals the acute CoBF reduction after CAO was unaltered, and the recovery was even accelerated as compared to controls. These results indicate that (i) the Willis circle alone is not sufficient to provide an immediate compensation for the loss of one carotid artery, (ii) pial collaterals attenuate the ischemia of the temporal cortex ipsilateral to CAO at the expense of the blood supply of the frontoparietal region, and (iii) eNOS, surprisingly, does not play an important role in this CoBF redistribution

A PUMA-G receptor élettani és kórélettani szerepe az agyi vérkeringésben. = Role of the PUMA-G receptor in the cerebral circulation.

Eredményeink szerint a PUMA-G receptor nem játszik szignifikáns szerepet az agykérgi véráramlás szabályozásában sem élettani sem pedig kórélettani körülmények között. Igazoltuk az epidermális Langerhans-sejtek szerepét a nikotinsav-okozta flush- reakció a közvetíttésében, mely adatok egyúttal arra utalnak, hogy a Langerhans-sejteknek élettani/kórélettani szerepe lehet a bőr véráramlásának szabályozásában. Eredményeink szerint a nikotinsav a PUMA-G receptor által közvetített mechanizmussal csökkenti a sebocyták zsírtartalmát egérben, ami felveti a PUMA-G receptor agonisták alkalmazásának lehetőségét az acne és seborrhea kezelésére. Leírtuk, hogy hypoxia és hypercapnia során az endocannabinoid felszabadulás agykérgi véráramlás-csökkenést okoz, aminek hátterében az excitatorikus glutamáterg neurotranszmisszió preszinaptikus gátlását feltételezzük. Igazoltuk, hogy az endogén CO képződés egyrészt tónusosan gátolja a hypothalamikus nitrogén monoxid szintetáz (NOS) aktivitást, másrészt pedig stimulálja a PGE2?felszabadulást és e két úton keresztül indirekt módon képes befolyásolni a hypothalamus véráramlását. Más agyi régiókban, pl. a parietális agykéregben az endogén CO NOS-t gátló hatása dominál és így véráramlás-csökkenést okoz. Megállapítottuk, hogy a neutrális szfingomielináz reaktív oxigén szabadgyökök által közvetített, de NOX2-től független módon csökkenti az a. carotis kontrakciós válaszait. | Our results indicate that the PUMA-G receptor has no significant role in the regulation of the cerebrocortical blood flow under physiological or pathophysiological conditions. We proved that epidermal Langerhans-cells mediate the nicotinic acid induced flush reaction indicating that these cells may play important roles in the regulation of the dermal blood flow. Nicotinic acid inhibits lipogenesis in sebocytes which effect is mediated by the PUMA-G receptor. Therefore, PUMA-G agonists may be beneficial in the treatment of seborrhea and acne. We described that endogenous CO suppresses hypothalamic NOS activity but stimulates PGE2-release at the same time. Both of these effects indirectly influence the hypothalamic circulation. In the parietal cortex CO reduces blood flow via inhibition of NO synthesis. In preliminary experiments we found that neutral sphingomyelinase suppresses the contractile responses of the carotid artery via NOX2-independent generation of reactive oxygen species

Oleuropein effects on rat and human microcirculation

The aim of the present study was to investigate oleuropein effects on microvascular responses. First, we investigated the in vivo effects of oleuropein on rat pial microcirculation submitted to hypoperfusion-reperfusion injury. Therefore, we studied acute microvascular responses such as arteriolar vasodilation, permeability increase, leukocyte adhesion and capillary perfusion, by fluorescence microscopy. The working hypothesis was that this polyphenol may induce nitric oxide (NO) release from endothelial cells and consequently protect cerebral blood flow distribution and cerebral tissue. Rat cerebral cortical eNOS protein levels were evaluated as well as the impact of oxidative stress induced by hypopefusion and reperfusion on brain tissue, utilizing DCFH-DA. The second part of the study was aimed to evaluate oleuropein effects on skin microvascular blood flow oscillations of hyperlipidemic obese patients, by laser Doppler flowmetry (LDF). Therefore, hyperlipidemic obese females were administered with a hypocaloric and hypolipidic diet plus oleuropein for three months. These data were compared with the response of hyperlipidemic obese patients administered with hypocaloric and hypolipidic diet. Under baseline conditions and at the end of the study, nutritional status and lipid profile were evaluated as well as skin blood flow oscillations and reactive hyperemia by LDF. The results of the experimental study in rats indicate that oleuropein significantly improved in vivo microvascular responses after hypoperfusion-reperfusion injury. In particular, 20 mg/Kg b.w. of oleuropein induced a dilation by 28 ±2% of baseline (p < 0.01 vs. hypoperfused group) in order 3 arterioles and significantly reduced microvascular leakage (NGL: 0.13 ± 0.03; p < 0.01 vs. hypoperfused group) as well as leukocyte adhesion on venular walls (2.0 ± 0.5/100 µm v.l./30 sec; p < 0.01 vs. hypoperfused group), at the end of reperfusion. Moreover, this polyphenol was able to preserve capillary perfusion at the end of reperfusion (-26.0±4.5% of baseline; p<0.01 vs. hypoperfused group). These responses were associated to the increased eNOS expression in cortex and in striatum of treated animals. Oleuropein was also able to reduce neuronal damage and ROS production at the end of reperfusion, compared with hypoperfused animals. On the other hand, the results of the clinical study revealed that three months of hypocaloric and hypolipidic diet associated to oleuropein significantly improved nutritional status and lipid profile of hyperlipidemic obese patients. Total and LDL cholesterol, indeed, decreased by 15.0±1.2 and 16.5±1.3%, respectively, in patients treated with diet (OD group), and by 21.3±1.5 and 21.2±1.4%, respectively, in subjects treated with diet plus oleuropein (OL group). Moreover, laser Doppler measurements showed an increase in skin perfusion, compared to baseline conditions and control group (+25.6±1.4% of baseline), while the spectral analysis of skin blood flow oscillations revealed an increase in the NO-dependent and myogenic-related frequency components. Furthermore, PORH response improved in oleuropein-treated group, compared to controls. In conclusion, oleuropein appeared able to protect rat pial microcirculation from hypoperfusion-reperfusion injury increasing nitric oxide release from endothelial cells, reducing oxidative stress and, consequently, preserving pial blood flow distribution. Interestingly, this polyphenol showed beneficial effects also in humans; three months of hypocaloric and hypolipidic diet plus oleuropein increased smooth muscle cell functions and microvascular responses in hyperlipidemic obese patients, improving tissue perfusion

Rat pial microvascular responses to melatonin during bilateral common carotid artery occlusion and reperfusion

The present study assessed the in vivo rat pial microvascular responses induced by melatonin during brain hypoperfusion and reperfusion (RE) injury. Pial microcirculation of male Wistar rats was visualized by fluorescence microscopy through a closed cranial window. Hypoperfusion was induced by bilateral common carotid artery occlusion (BCCAO, 30 min); thereafter, pial microcirculation was observed for 60 min. Arteriolar diameter, permeability increase, leukocyte adhesion to venular walls, perfused capillary length (PCL), and capillary red blood cell velocity (V(RBC) ) were investigated by computerized methods. Melatonin (0.5, 1, 2 mg/kg b.w.) was intravenously administered 10 min before BCCAO and at the beginning of RE. Pial arterioles were classified in five orders according to diameter, length, and branchings. In control group, BCCAO caused decrease in order 2 arteriole diameter (by 17.5 ± 3.0% of baseline) that was reduced by 11.8 ± 1.2% of baseline at the end of RE, accompanied by marked leakage and leukocyte adhesion. PCL and capillary V(RBC) decreased. At the end of BCCAO, melatonin highest dosage caused order 2 arteriole diameter reduction by 4.6 ± 2.0% of baseline. At RE, melatonin at the lower dosages caused different arteriolar responses. The highest dosage caused dilation in order 2 arteriole by 8.0 ± 1.5% of baseline, preventing leakage and leukocyte adhesion, while PCL and V(RBC) increased. Luzindole (4 mg/kg b.w.) prior to melatonin caused order 2 arteriole constriction by 12.0 ± 1.5% of baseline at RE, while leakage, leukocyte adhesion, PCL and V(RBC) were not affected. Prazosin (1 mg/kg b.w.) prior to melatonin did not significantly change melatonin's effects. In conclusion, melatonin caused different responses during hypoperfusion and RE, modulating pial arteriolar tone likely by MT1 and MT2 melatonin receptors while preventing blood-brain barrier changes through its free radical scavenging action

Vasomotion and Neurovascular Coupling in the Visual Thalamus In Vivo

Spontaneous contraction and relaxation of arteries (and in some instances venules) has been termed vasomotion and has been observed in an extensive variety of tissues and species. However, its functions and underlying mechanisms are still under discussion. We demonstrate that in vivo spectrophotometry, measured simultaneously with extracellular recordings at the same locations in the visual thalamus of the cat, reveals vasomotion, measured as an oscillation (0.14hz) in the recorded oxyhemoglobin (OxyHb) signal, which appears spontaneously in the microcirculation and can last for periods of hours. During some non-oscillatory periods, maintained sensory stimulation evokes vasomotion lasting ∼30s, resembling an adaptive vascular phenomenon. This oscillation in the oxyhaemoblobin signal is sensitive to pharmacological manipulation: it is inducible by chloralose anaesthesia and it can be temporarily blocked by systemic administration of adrenaline or acetylcholine (ACh). During these oscillatory periods, neurovascular coupling (i.e. the relationship between local neural activity and the rate of blood supply to that location) appears significantly altered. This raises important questions with regard to the interpretation of results from studies currently dependent upon a linear relationship between neural activity and blood flow, such as neuroimaging

Inversion of neurovascular coupling after subarachnoid hemorrhage in vivo

Subarachnoid hemorrhage (SAH) induces acute changes in the cerebral microcirculation. Recent findings ex vivo suggest neurovascular coupling (NVC), the process that increases cerebral blood flow upon neuronal activity, is also impaired after SAH. The aim of the current study was to investigate whether this occurs also invivo. C57BL/6 mice were subjected to either sham surgery or SAH by filament perforation. Twenty-four hours later NVC was tested by forepaw stimulation and CO2 reactivity by inhalation of 10% CO2. Vessel diameter was assessed invivo by two-photon microscopy. NVC was also investigated ex vivo using brain slices. Cerebral arterioles of sham-operated mice dilated to 130% of baseline upon CO2 inhalation or forepaw stimulation and cerebral blood flow (CBF) increased. Following SAH, however, CO2 reactivity was completely lost and the majority of cerebral arterioles showed paradoxical constriction invivo and ex vivo resulting in a reduced CBF response. As previous results showed intact NVC 3h after SAH, the current findings indicate that impairment of NVC after cerebral hemorrhage occurs secondarily and is progressive. Since neuronal activity-induced vasoconstriction (inverse NVC) is likely to further aggravate SAH-induced cerebral ischemia and subsequent brain damage, inverse NVC may represent a novel therapeutic target after SAH

A Model for Transient Oxygen Delivery in Cerebral Cortex

Popular hemodynamic brain imaging methods, such as blood oxygen-level dependent functional magnetic resonance imaging (BOLD fMRI), would benefit from a detailed understanding of the mechanisms by which oxygen is delivered to the cortex in response to brief periods of neural activity. Tissue oxygen responses in visual cortex following brief visual stimulation exhibit rich dynamics, including an early decrease in oxygen concentration, a subsequent large increase in concentration, and substantial late-time oscillations (“ringing”). We introduce a model that explains the full time-course of these observations made by Thompson et al. (2003). The model treats oxygen transport with a set of differential equations that include a combination of flow and diffusion in a three-compartment (intravascular, extravascular, and intracellular) system. Blood flow in this system is modeled using the impulse response of a lumped linear system that includes an inertive element; this provides a simple biophysical mechanism for the ringing. The model system is solved numerically to produce excellent fits to measurements of tissue oxygen. The results give insight into the dynamics of cerebral oxygen transfer, and can serve as the starting point to understand BOLD fMRI measurements

Basic and Clinical Understanding of Microcirculation

Microcirculation is key to providing enough nutrition and oxygen from head to toe. This is possible only through an extensive network of blood vessels spread around the body. Effect of microcirculation abnormalities stretch beyond one’s comprehension. The effects could be felt at any age, from the foetal life to the adulthood. The chapters present in this book describe how these abnormalities could lead to diseases such as atherosclerosis, thrombosis, diabetes, hypertension. Disorders of microcirculation could be related to the structural and/or functional damage to the inner lining of the blood vessels. Early identification of these disorders could benefit many ailments including cardiovascular and cerebrovascular diseases such as heart attack and stroke