Blood–spinal cord barrier pericyte reductions contribute to increased capillary permeability

The blood–spinal cord barrier (BSCB) regulates molecular exchange between blood and spinal cord. Pericytes are presumed to be important cellular constituents of the BSCB. However, the regional abundance and vascular functions of spinal cord pericytes have yet to be determined. Utilizing wild-type mice, we show that spinal cord pericyte capillary coverage and number compared with the brain regions are reduced most prominently in the anterior horn. Regional pericyte variations are highly correlated with: (1) increased capillary permeability to 350 Da, 40,000 Da, and 150,000 Da, but not 2,000,000 Da fluorescent vascular tracers in cervical, thoracic, and lumbar regions and (2) diminished endothelial zonula occludens-1 (ZO-1) and occludin tight junction protein expression. Pericyte-deficient mutations (Pdgfrβ F7/F7 mice) resulted in additional pericyte reductions in spinal cord capillaries leading to overt BSCB disruption to serum proteins, accumulation in motor neurons of cyotoxic thrombin and fibrin and motor neuron loss. Barrier disruption in perciyte-deficient mice coincided with further reductions in ZO-1 and occludin. These data suggest that pericytes contribute to proper function of the BSCB at the capillary level. Regional reductions in spinal cord pericytes may provide a cellular basis for heightened spinal cord barrier capillary permeability and motor neuron loss.

[1]  Lee D. Hallagan,et al.  Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. , 2009, The Journal of clinical investigation.

[2]  Bengt R. Johansson,et al.  Pericytes regulate the blood–brain barrier , 2010, Nature.

[3]  P. M. Daniel,et al.  Comparison of the Vascular Permeability of the Brain and the Spinal Cord to Mannitol and Inulin in Rats , 1985, Journal of neurochemistry.

[4]  B R Johansson,et al.  Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. , 1997, Science.

[5]  D. Attwell,et al.  Bidirectional control of CNS capillary diameter by pericytes , 2006, Nature.

[6]  Holger Gerhardt,et al.  Lack of Pericytes Leads to Endothelial Hyperplasia and Abnormal Vascular Morphogenesis , 2001, The Journal of cell biology.

[7]  W. Banks,et al.  Permeability of the blood–brain and blood–spinal cord barriers to interferons , 1997, Journal of Neuroimmunology.

[8]  P. Sanberg,et al.  Amyotrophic lateral sclerosis: A neurovascular disease , 2011, Brain Research.

[9]  R. Deane,et al.  ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration , 2008, Nature Neuroscience.

[10]  S. Strickland,et al.  Neuronal Death in the Hippocampus Is Promoted by Plasmin-Catalyzed Degradation of Laminin , 1997, Cell.

[11]  B. Zlokovic,et al.  Central nervous system pericytes in health and disease , 2011, Nature Neuroscience.

[12]  W. Banks,et al.  Blood–Brain Barrier Permeability to Ebiratide and TNF in Acute Spinal Cord Injury , 1997, Experimental Neurology.

[13]  H. Hammes,et al.  Endothelium‐specific platelet‐derived growth factor‐B ablation mimics diabetic retinopathy , 2002, The EMBO journal.

[14]  Ulrich Dirnagl,et al.  Pericytes in capillaries are contractile in vivo, but arterioles mediate functional hyperemia in the mouse brain , 2010, Proceedings of the National Academy of Sciences.

[15]  Berislav V. Zlokovic,et al.  Pericytes Control Key Neurovascular Functions and Neuronal Phenotype in the Adult Brain and during Brain Aging , 2010, Neuron.

[16]  R. Deane,et al.  Protein S controls hypoxic/ischemic blood-brain barrier disruption through the TAM receptor Tyro3 and sphingosine 1-phosphate receptor. , 2010, Blood.

[17]  B. Zlokovic.  Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders , 2011, Nature Reviews Neuroscience.

[18]  J. Pachter,et al.  Isolation and culture of microvascular endothelial cells from murine spinal cord , 2006, Journal of Neuroimmunology.

[19]  M. Apuzzo,et al.  Cellular and molecular neurosurgery: pathways from concept to reality--part I: target disorders and concept approaches to gene therapy of the central nervous system. , 1997, Neurosurgery.

[20]  L. Prockop,et al.  Selective permeability of [3H]-D-mannitol and [14C]-carboxyl-inulin across the blood-brain barrier and blood-spinal cord barrier in the rabbit. , 1995, The journal of spinal cord medicine.

[21]  Philippe Soriano,et al.  Additive Effects of PDGF Receptor β Signaling Pathways in Vascular Smooth Muscle Cell Development , 2003, PLoS biology.

[22]  H. Hammes,et al.  Pericyte migration : A novel mechanism of pericyte loss in experimental diabetic retinopathy , 2008 .

[23]  B. Zlokovic,et al.  Differential regulation of leptin transport by the choroid plexus and blood-brain barrier and high affinity transport systems for entry into hypothalamus and across the blood-cerebrospinal fluid barrier. , 2000, Endocrinology.

[24]  R. Gutiérrez,et al.  Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. , 2009, Histology and histopathology.

[25]  B. Zlokovic.  The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders , 2008, Neuron.

[26]  B. Zlokovic,et al.  Evidence for a lactate transport system in the sarcolemmal membrane of the perfused rabbit heart: kinetics of unidirectional influx, carrier specificity and effects of glucagon. , 1985, Biochimica et biophysica acta.

[27]  C. Betsholtz,et al.  Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. , 2011, Developmental cell.

[28]  Berislav V. Zlokovic,et al.  Apolipoprotein E controls cerebrovascular integrity via cyclophilin A , 2012, Nature.

[29]  O. Shupliakov,et al.  A Pericyte Origin of Spinal Cord Scar Tissue , 2011, Science.

[30]  B. Barres,et al.  Pericytes are required for blood–brain barrier integrity during embryogenesis , 2010, Nature.

[31]  P. Grammas,et al.  Thrombin, a mediator of neurotoxicity and memory impairment , 2004, Neurobiology of Aging.

[32]  D. Jezova,et al.  The blood–spinal cord barrier: Morphology and Clinical Implications , 2011, Annals of neurology.

[33]  J. Melchor,et al.  Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease. , 2007 .

[34]  B. Zlokovic,et al.  Differential expression of Na,K-ATPase alpha and beta subunit isoforms at the blood-brain barrier and the choroid plexus. , 1993, The Journal of biological chemistry.

[35]  Youliang Wang,et al.  Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch. , 2011, Developmental cell.

[36]  C. Hoogenraad,et al.  Neuron-Specific Expression of Mutant Superoxide Dismutase Is Sufficient to Induce Amyotrophic Lateral Sclerosis in Transgenic Mice , 2008, The Journal of Neuroscience.

[37]  J. Bading,et al.  Cerebrovascular Accumulation and Increased Blood‐Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy , 1998, Journal of neurochemistry.

[38]  J. Greenwood,et al.  Blood‐brain barrier‐specific properties of a human adult brain endothelial cell line , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  B. Zlokovic,et al.  Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling , 2010, Molecular Neurodegeneration.

[40]  Jin Hyoung Kim,et al.  Recruitment of pericytes and astrocytes is closely related to the formation of tight junction in developing retinal vessels , 2008, Journal of neuroscience research.