Pericytes impair capillary blood flow and motor function after chronic spinal cord injury
Yaqing Li, Ana M Lucas-Osma, Sophie Black, Mischa V Bandet, Marilee J Stephens, Romana Vavrek, Leo Sanelli, Keith K Fenrich, Antonio F Di Narzo, Stella Dracheva, Ian R Winship, Karim Fouad, David J Bennett, Yaqing Li, Ana M Lucas-Osma, Sophie Black, Mischa V Bandet, Marilee J Stephens, Romana Vavrek, Leo Sanelli, Keith K Fenrich, Antonio F Di Narzo, Stella Dracheva, Ian R Winship, Karim Fouad, David J Bennett
Abstract
Blood vessels in the central nervous system (CNS) are controlled by neuronal activity. For example, widespread vessel constriction (vessel tone) is induced by brainstem neurons that release the monoamines serotonin and noradrenaline, and local vessel dilation is induced by glutamatergic neuron activity. Here we examined how vessel tone adapts to the loss of neuron-derived monoamines after spinal cord injury (SCI) in rats. We find that, months after the imposition of SCI, the spinal cord below the site of injury is in a chronic state of hypoxia owing to paradoxical excess activity of monoamine receptors (5-HT1) on pericytes, despite the absence of monoamines. This monoamine-receptor activity causes pericytes to locally constrict capillaries, which reduces blood flow to ischemic levels. Receptor activation in the absence of monoamines results from the production of trace amines (such as tryptamine) by pericytes that ectopically express the enzyme aromatic L-amino acid decarboxylase (AADC), which synthesizes trace amines directly from dietary amino acids (such as tryptophan). Inhibition of monoamine receptors or of AADC, or even an increase in inhaled oxygen, produces substantial relief from hypoxia and improves motoneuron and locomotor function after SCI.
Figures
References
- Acker T, Acker H. Cellular oxygen sensing need in CNS function: physiological and pathological implications. J Exp Biol. 2004;207:3171–3188.
- Martirosyan NL, et al. Blood supply and vascular reactivity of the spinal cord under normal and pathological conditions. J Neurosurg Spine. 2011;15:238–251.
- Pena F, Ramirez JM. Hypoxia-induced changes in neuronal network properties. Mol Neurobiol. 2005;32:251–283.
- Hamilton NB, Attwell D, Hall CN. Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front Neuroenergetics. 2010;2
- Itoh Y, Suzuki N. Control of brain capillary blood flow. J Cereb Blood Flow Metab. 2012;32:1167–1176.
- Peppiatt CM, Howarth C, Mobbs P, Attwell D. Bidirectional control of CNS capillary diameter by pericytes. Nature. 2006;443:700–704.
- Reber F, Gersch U, Funk RW. Blockers of carbonic anhydrase can cause increase of retinal capillary diameter, decrease of extracellular and increase of intracellular pH in rat retinal organ culture. Graefes Arch Clin Exp Ophthalmol. 2003;241:140–148.
- Barcroft H, Bonnar WM, Edholm OG, Effron AS. On sympathetic vasoconstrictor tone in human skeletal muscle. J Physiol. 1943;102:21–31.
- Westcott EB, Segal SS. Perivascular innervation: a multiplicity of roles in vasomotor control and myoendothelial signaling. Microcirculation. 2013;20:217–238.
- Bonvento G, et al. Evidence for differing origins of the serotonergic innervation of major cerebral arteries and small pial vessels in the rat. J Neurochem. 1991;56:681–689.
- Cohen Z, Bonvento G, Lacombe P, Hamel E. Serotonin in the regulation of brain microcirculation. Prog Neurobiol. 1996;50:335–362.
- Cohen Z, Molinatti G, Hamel E. Astroglial and vascular interactions of noradrenaline terminals in the rat cerebral cortex. J Cereb Blood Flow Metab. 1997;17:894–904.
- Lincoln J. Innervation of cerebral arteries by nerves containing 5-hydroxytryptamine and noradrenaline. Pharmacol Ther. 1995;68:473–501.
- Hardebo JE, Owman C. Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface. Ann Neurol. 1980;8:1–31.
- Murray KC, et al. Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nat Med. 2010;16:694–700.
- Brown A, Nabel A, Oh W, Etlinger JD, Zeman RJ. Perfusion imaging of spinal cord contusion: injury-induced blockade and partial reversal by beta2-agonist treatment in rats. J Neurosurg Spine. 2014;20:164–171.
- Kang CE, Clarkson R, Tator CH, Yeung IW, Shoichet MS. Spinal cord blood flow and blood vessel permeability measured by dynamic computed tomography imaging in rats after localized delivery of fibroblast growth factor. J Neurotrauma. 2010;27:2041–2053.
- Sinescu C, et al. Molecular basis of vascular events following spinal cord injury. J Med Life. 2010;3:254–261.
- Kundi S, Bicknell R, Ahmed Z. The role of angiogenic and wound-healing factors after spinal cord injury in mammals. Neurosci Res. 2013;76:1–9.
- Murray KC, et al. Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F receptors. J Neurophysiol. 2011;106:925–943.
- Rank MM, et al. Adrenergic receptors modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic spinal cord injury. J Neurophysiol. 2011;105:410–422.
- Commissiong JW. The synthesis and metabolism of catecholamines in the spinal cord of the rat after acute and chronic transections. Brain Res. 1985;347:104–111.
- Li Y, et al. Synthesis, transport, and metabolism of serotonin formed from exogenously applied 5-HTP after spinal cord injury in rats. J Neurophysiol. 2014;111:145–163.
- Wienecke J, et al. Spinal cord injury enables aromatic L-amino acid decarboxylase cells to synthesize monoamines. J Neurosci. 2014;34:11984–12000.
- Berry MD. Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators. J Neurochem. 2004;90:257–271.
- Burchett SA, Hicks TP. The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain. Prog Neurobiol. 2006;79:223–246.
- Gozal EA, et al. Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord. Front Neural Circuits. 2014;8:134.
- Glaeser BS, Maher TJ, Wurtman RJ. Changes in brain levels of acidic, basic, and neutral amino acids after consumption of single meals containing various proportions of protein. J Neurochem. 1983;41:1016–1021.
- Gessa GL, Biggio G, Fadda F, Corsini GU, Tagliamonte A. Effect of the oral administration of tryptophan-free amino acid mixtures on serum tryptophan, brain tryptophan and serotonin metabolism. J Neurochem. 1974;22:869–870.
- Hawkins RA, O'Kane RL, Simpson IA, Vina JR. Structure of the blood-brain barrier and its role in the transport of amino acids. J Nutr. 2006;136:218S–226S.
- Boess FG, Martin IL. Molecular biology of 5-HT receptors. Neuropharmacology. 1994;33:275–317.
- U'Prichard DC, Greenberg DA, Snyder SH. Binding characteristics of a radiolabeled agonist and antagonist at central nervous system alpha noradrenergic receptors. Mol Pharmacol. 1977;13:454–473.
- Bunzow JR, et al. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001;60:1181–1188.
- Anwar MA, Ford WR, Broadley KJ, Herbert AA. Vasoconstrictor and vasodilator responses to tryptamine of rat-isolated perfused mesentery: comparison with tyramine and beta-phenylethylamine. Br J Pharmacol. 2012;165:2191–2202.
- Broadley KJ, Fehler M, Ford WR, Kidd EJ. Functional evaluation of the receptors mediating vasoconstriction of rat aorta by trace amines and amphetamines. Eur J Pharmacol. 2013;715:370–380.
- Cohen Z, et al. Multiple microvascular and astroglial 5-hydroxytryptamine receptor subtypes in human brain: molecular and pharmacologic characterization. J Cereb Blood Flow Metab. 1999;19:908–917.
- Rennels ML, Nelson E. Capillary innervation in the mammalian central nervous system: an electron microscopic demonstration. Am J Anat. 1975;144:233–241.
- Busija DW, Leffler CW. Postjunctional alpha 2-adrenoceptors in pial arteries of anesthetized newborn pigs. Dev Pharmacol Ther. 1987;10:36–46.
- Edvinsson L, Degueurce A, Duverger D, MacKenzie ET, Scatton B. Central serotonergic nerves project to the pial vessels of the brain. Nature. 1983;306:55–57.
- Attwell D, et al. Glial and neuronal control of brain blood flow. Nature. 2010;468:232–243.
- Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nat Neurosci. 2011;14:1398–1405.
- Xiong Z, Sperelakis N. Regulation of L-type calcium channels of vascular smooth muscle cells. J Mol Cell Cardiol. 1995;27:75–91.
- Goritz C, et al. A pericyte origin of spinal cord scar tissue. Science. 2011;333:238–242.
- Dalkara T, Gursoy-Ozdemir Y, Yemisci M. Brain microvascular pericytes in health and disease. Acta Neuropathol. 2011;122:1–9.
- Hall CN, et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014;508:55–60.
- Burdyga T, Borysova L. Calcium signalling in pericytes. J Vasc Res. 2014;51:190–199.
- Narzo AF, et al. Decrease of mRNA Editing after Spinal Cord Injury is Caused by Down-regulation of ADAR2 that is Triggered by Inflammatory Response. Sci Rep. 2015;5:12615.
- Unekawa M, et al. RBC velocities in single capillaries of mouse and rat brains are the same, despite 10-fold difference in body size. Brain Res. 2010;1320:69–73.
- Carreau A, El Hafny-Rahbi B, Matejuk A, Grillon C, Kieda C. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med. 2011;15:1239–1253.
- Marina N, et al. Brainstem hypoxia contributes to the development of hypertension in the spontaneously hypertensive rat. Hypertension. 2015;65:775–783.
- Schroeder JL, Highsmith JM, Young HF, Mathern BE. Reduction of hypoxia by perfluorocarbon emulsion in a traumatic spinal cord injury model. J Neurosurg Spine. 2008;9:213–220.
- Wilson RJ, Chersa T, Whelan PJ. Tissue PO2 and the effects of hypoxia on the generation of locomotor-like activity in the in vitro spinal cord of the neonatal mouse. Neuroscience. 2003;117:183–196.
- van den Brand R, et al. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science. 2012;336:1182–1185.
- Attwell D, Mishra A, Hall CN, O'Farrell FM, Dalkara T. What is a pericyte? J Cereb Blood Flow Metab. 2016;36:451–455.
- Hill RA, et al. Regional Blood Flow in the Normal and Ischemic Brain Is Controlled by Arteriolar Smooth Muscle Cell Contractility and Not by Capillary Pericytes. Neuron. 2015;87:95–110.
- Gorassini MA, Norton JA, Nevett-Duchcherer J, Roy FD, Yang JF. Changes in locomotor muscle activity after treadmill training in subjects with incomplete spinal cord injury. J Neurophysiol. 2009;101:969–979.
- Kapitza S, et al. Tail spasms in rat spinal cord injury: changes in interneuronal connectivity. Exp Neurol. 2012;236:179–189.
- Beauparlant J, et al. Undirected compensatory plasticity contributes to neuronal dysfunction after severe spinal cord injury. Brain. 2013;136:3347–3361.
- Navarrete-Opazo A, Mitchell GS. Therapeutic potential of intermittent hypoxia: a matter of dose. Am J Physiol Regul Integr Comp Physiol. 2014;307:R1181–1197.
- Miller GM. The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity. J Neurochem. 2011;116:164–176.
Source: PubMed