Abstracts from the 10Th World Congress for Microcirculation

DOI:10.1111/micc.12246 Abstracts Abstracts from the 10th World Congress for Microcirculation September 25th – 27th, 2015 Kyoto, Japan PLENARY LECTURES vascular neutrophils that constantly patrol the lung and can detect and phagocytose bacteria attached to endothelium suggesting some communication inter-cellular communica- PL1 tion. Clearly much anti-microbial activity occurs in the Imaging the microcirculation in infections vasculature prior to dissemination of bacteria into tissues. P Kubes University of Calgary, Calgary, Canada PL2 Using spinning disk microscopy has allowed us to track pathogens and immune cells in the microcirculation. Mapping oxygen in the brain of awake resting Observing the liver microvasculature revealed numerous mice immune speed bumps that slowed, delayed and even S Charpak prevented bacteria from disseminating to other organs. For Laboratory of Neurophysiology and New Microscopies, Inserm U1128, example, when Borrelia burgdorferi enters the vasculature Paris Descartes University, Paris, France they are immediately caught by the liver vascular macro- The brain is extremely sensitive to hypoxia. Yet, the phage, the Kupffer cells and are engulfed and antigens are physiological values of oxygen concentration in the brain presented on CD1d to resident vascular immune cells remain elusive because high resolution measurements have including invariant Natural Killer T cells (iNKT cells). These only been performed during anesthesia, which affects two iNKT cells receive messages and rapidly make gamma main parameters modulating tissue oxygenation, i.e. interferon to help with immunity. Absence of these events neuronal activity and cerebral blood flow. Using the recent leads to massive dissemination of borrelia especially to joints. finding that measurements of capillary erythrocyte-associ- In the joints the iNKT cells live closely apposed but outside ated transients i.e. micron-scale fluctuations of oxygen the vasculature and prevent borrelia from infiltrating. They partial pressure (Po2) associated with individual erythrocytes, appear to kill the borrelia as they try to breach the barrier can be used to infer Po2 in nearby neuropil, we non- and enter tissues. Staphylococcus aureus is able to survive in invasively mapped Po2 and blood flow parameters in the the vasculature inside Kupffer cells avoiding neutrophils and brain of awake, resting mice. We find region- and layer- proliferating intracellularly. Oxidants but not proteases limit specific differences in tissue Po2, hematocrit and blood flow. but do not eradicate this pathogen inside Kupffer cells. The Tissue Po2 at rest is 23 mm Hg on average, ranges from few bacteria cause the Kupffer cells to lyse and the bacteria to 50 mm Hg, but doubles with isoflurane anesthesia. This emerge where neutrophils are now poised and ready to catch study emphasizes the importance of measurements in bacteria via neutrophil extracellular traps (NETs). The NETs physiological conditions to determine the safe margin of are able to catch the bacteria but some may escape and reach brain oxygenation and to model brain metabolism. kidneys. We have also noted that as long as the S.aureus remains hidden in Kupffer cells it is protected from antibiotics so we are designing novel ways of delivering anti-microbial agents into Kupffer cells. Some bacteria like Streptococcus pneumonia evades the Kupffer cells but are caught in spleen by different specialized macrophage and neutrophils and also adhere to the endothelium in lung vasculature. In the lung we have a resident population of ª 2015 John Wiley & Sons Ltd 1 Abstracts PL3 possess an abundance of functional ATP-sensitive potassium Angiogenesis revisited: Endothelial cell (KATP) channels, but only a paucity of voltage-dependent metabolism as a target? calcium channels (VDCCs); on the other hand, the converse P Carmeliet is the case for pre-capillary arterioles. This specialization is Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research likely to enhance the decentralized regulation of retinal blood Center, Leuven, Belgium, Department of Oncology, KU Leuven, Leuven, flow. Importantly, physiological differences within the retinal Belgium microvasculature have important pathobiological implica- Angiogenesis, the growth of new blood vessels, plays a crucial tions. Namely, the presence of KATP channels and absence of role in numerous diseases, including cancer. Anti-angiogen- VDCCs almost completely accounts for why pericyte- esis therapies have been developed to starve cancer cells from containing retinal capillaries are far more vulnerable than nutrients. Clinically approved anti-angiogenic drugs prolong arterioles to pathophysiological conditions of the diabetic the survival of cancer patients, but their success is limited by retina such as hypoxia, ischemia, oxidative stress and intrinsic refractoriness and acquired resistance. New strate- purinergic vasotoxicity. Thus, the concept is emerging that gies are thus needed to block tumor angiogenesis via the pathophysiology of pericyte-containing retinovessels is alternative mechanisms. We recently reported that closely linked with their physiology. PFKFB3-driven glycolysis regulates the endothelial tip cell function during vessel sprouting, even capable of overruling the potent pro-stalk activity of Notch, and that its loss in S1-2 endothelial cells causes vascular hypobranching defects. Pacemaker role of pericytes in the Moreover, partial and transient reduction of glycolysis by microvasculature of visceral organs blocking PFKFB3 reduced pathological angiogenesis in H Hashitani several disease models. Ongoing studies explore the role of Department of Cell Physiology, Graduate School of Medical Sciences, lipid and amino acid metabolism in vessel sprouting, and Nagoya City University, Nagoya, Japan assess the therapeutic potential of targeting these metabolic The importance of pericytes in regulating blood flow has pathways for anti-angiogenic therapy. been revealed in several vascular beds, but their functions in the microcirculation of visceral organs remains to be SYMPOSIUM determined. In visceral organs that undergo considerable distension upon filling, the microvasculature appears to S1-1 display intrinsic contractile properties. Submucosal venules Pericyte-containing retinovessels: The yin-yang of in the urinary bladder generate spontaneous constrictions their physiology and pathobiology triggered upon the firing of spontaneous Ca2+ transients and DG Puro transient depolarisations. These events are initiated within 2+ Departments of Ophthalmology & Vision Sciences and Molecular & venular pericytes upon the spontaneous Ca release from 2+ Integrative Physiology, University of Michigan, USA sarcoplasmic reticulum (SR) and the opening of Ca - activated chloride channels that trigger Ca2+ influx through Pericyte-containing microvessels constitute the largest por- L-type voltage-dependent Ca2+ channels (VDCC). These tion of the vascular system. Although present in nearly all L-type VDCC play a critical role in maintaining synchrony tissues, this component of the microvasculature is likely to be within venular pericytes. In the stomach myenteric layer, particularly important in the retina where the density of highly-synchronous spontaneous Ca2+ transients are evident abluminal pericytes is greater than anywhere else. The in both arteriolar smooth muscle cells (SMCs) and capillary multitude of pericytes appears essential for the highly pericytes of the microvasculature tree. Spontaneous Ca2+ decentralized and autoregulated control of blood flow that transients initiated in capillary pericytes appear to spread to occurs in the retina. Pericyte-containing microvessels are not their neighbouring arteriolar SMCs. Capillary Ca2+ transients only important in retinal physiology, but also in pathobiol- primarily rely on spontaneous SR Ca2+ release, but also ogy. For example, pericyte loss is an early hallmark of the require Ca2+ influx through T-type VDCC for their syn- major sight-threatening disorder, diabetic retinopathy. In chrony. The opening of T-type VDCC may also contribute to our studies, we focus on the role of ion channels in the the Ca2+ transients that propagate into arteriolar SMCs. physiology and pathobiology of pericyte-containing capillar- Thus, pericytes in the visceral microvasculature may act as ies and pre-capillary arterioles, which together constitute the the originators of synchronous spontaneous Ca2+ transients most decentralized operational unit in the retinal vascula- that regulate contractility of “upstream” arterioles and ture. We discovered that there is physiological specialization “downstream” venules so that the microcirculation blood within the capillary/arteriole unit. For example, capillaries flow meets tissue demand. Pericytes in the microvasculature 2 ª 2015 John Wiley & Sons Ltd Abstracts appear to function as voltage-dependent coupled Ca2+ 1,4,5-trisphosphate receptor channels. The responses in per- oscillators, their synchrony depending on various VDCC icytes are less oscillatory, slower and longer-lasting than those types in a microvasculature bed-dependent manner. in myocytes. Myocytes and pericytes are electrically coupled, transmitting Ca2+ signals between arteriolar and venular networks dependent on gap junctions. Endothelial Ca2+ S1-3 signalling inhibits intracellular Ca2+ oscillations in myocytes The evolving role of renal pericytes and pericytes via L-arginine/NO/cGMP/PKG. There are C Peppiatt-Wildman physiological differences in the contractile

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