Elsevier

Brain Research

Volume 1623, 14 October 2015, Pages 3-17
Brain Research

Review
Cerebral microvascular pericytes and neurogliovascular signaling in health and disease

https://doi.org/10.1016/j.brainres.2015.03.047Get rights and content

Highlights

  • Communication between the elements of NVU is needed for neurovascular coupling.

  • Pericytes contribute to regulation of the microvascular blood flow and BBB integrity.

  • Pericyte–endothelia communication controls vasculogenesis and leukocyte infiltration.

  • Pericyte dysfunction may contribute to impaired reperfusion, diabetic retinopathy, and dementia.

  • Microvascular protection is essential for successful neuroprotection.

Abstract

Increases in neuronal activity cause an enhanced blood flow to the active brain area. This neurovascular coupling is regulated by multiple mechanisms: Adenosine and lactate produced as metabolic end-products couple activity with flow by inducing vasodilation. As a specific mechanism to the brain, synaptic activity-induced Ca2+ increases in astrocytes, interneurons and neurons translate neuronal activity to vasoactive signals such as arachidonic acid metabolites and NO. K+ released onto smooth muscle cells through Ca2+-activated K+ channels on end-feet can also induce vasodilation during neuronal activity. An intense communication between the endothelia, pericytes and astrocytes is required for development and functioning of the neurovascular unit as well as the BBB. The ratio of pericytes to endothelial cells is higher in the cerebral microcirculation than other tissues. Pericytes play a role in distribution of microvascular blood flow in response to the local demand as a final regulatory step after arterioles, which feed a larger cohort of cells. Pericyte–endothelial communication is essential for vasculogenesis. Pericyte also take part in leukocyte infiltration and immune responses. The microvascular injury induced by ischemia/reperfusion plays a critical role in tissue survival after recanalization by inducing sustained pericyte contraction and microcirculatory clogging (no-reflow) and by disrupting BBB integrity. Suppression of oxidative/nitrative stress or sustained adenosine delivery during re-opening of an occluded artery improves the outcome of recanalization by promoting microcirculatory reflow. Pericyte dysfunction in retinal microvessels is the main cause of diabetic retinopathy. Recent findings suggest that the age-related microvascular dysfunction may initiate the neurodegenerative changes seen Alzheimer׳s dementia.

This article is part of a Special Issue entitled SI: Cell Interactions In Stroke.

Section snippets

Cerebral circulation

The brain surface is covered by a network of pial arteries and veins (Duvernoy et al., 1981). Arteries branching off the pial network dive in the brain, while intracortical veins surface and join to pial veins (Duvernoy et al., 1981, Lauwers et al., 2008) (Fig. 1). The honeycomb-like structure of pial arterial/arteriolar network allows redistribution of blood during activation of cortical columns to match the increased focal demand of the activated brain area via penetrating arteries (Blinder

Neurovascular unit and neurovascular coupling

The neurovascular unit (NVU), which is composed of the endothelia, pericytes, neurons and astrocyte end-feet, plays an integrating role in matching the metabolic demand with the blood flow in addition to the vasodilation induced by adenosine and lactate produced as end-products of the metabolic activity and by NO of endothelial origin (Fig. 3) (Abbott et al., 2006, Attwell et al., 2010, Iadecola, 2004, Ko et al., 1990, Li and Iadecola, 1994). Recent studies suggest that astrocytes play an

Pericytes

Pericytes are uniquely positioned within the NVU; they communicate with other cells of the NVU and regulate several microcirculatory functions such as maintenance of the blood–brain barrier (BBB) and basal lamina, regulation of the angiogenesis, immune responses and scar formation in addition to their role in control of the microvascular flow (Attwell et al., 2010, Göritz et al., 2011, Hamilton et al., 2010, Krueger and Bechmann, 2010, Thomas, 1999) (Fig. 4). They may also function as

Microvascular injury after recanalization therapies for stroke

Thrombolysis trials have unambiguously demonstrated the presence of a salvageable brain tissue after ischemic stroke (Donnan et al., 2011, Heiss, 2011). However, a short therapeutic time window limits the use of recanalization therapies for majority of stroke patients (Donnan et al., 2009, Lees et al., 2010). This brief therapeutic window is attributed to rapid loss of neuronal viability in the ischemic penumbra supported by collaterals (Del Zoppo et al., 2011, Donnan et al., 2011). However,

Incomplete microcirculatory reflow after recanalization

An impaired tissue reperfusion due to loss of microvascular patency (no-reflow phenomenon) was first noted after global and focal cerebral ischemia more than 50 years ago (Ames et al., 1968, Crowell and Olsson, 1972). Starting one hour after MCA occlusion, some of the capillaries show constrictions whereas pre-capillary arterioles generally remain open (Belayev et al., 2002, Little et al., 1976). Narrowed capillary lumina are filled with entrapped erythrocytes, leukocytes and fibrin-platelet

Pericyte dysfunction causes diabetic retinopathy

Diabetic retinopathy is characterized by occlusion of retinal microvessels, acellular capillaries, microaneurysms, breakdown of the blood–retinal barrier, hemorrhages, macular edema and angiogenesis (Willard and Herman, 2012). Pericyte loss in the retinal microvessels is a hallmark of diabetic retinopathy. Platelet-derived growth factor β (PDGFβ) knockout mice provided the first insight to the role of pericytes in diabetic retinopathy because their microvessels were devoid of pericytes and

Microvascular dysfunction as a cause of neurodegenerative diseases

Dementia had been attributed to age-related changes in major cerebral arteries until the second half of 20th century when the interest shifted to deficiency in cholinergic innervation of the hippocampus and neocortex as well as to cerebral amyloid metabolism. However, the vascular hypothesis has recently been reawakened but, this time, based on the discoveries at microcirculatory level (Brown and Thore, 2011, De la Torre and Mussivand, 1993, Iadecola, 2010, Iadecola, 2004, Stanimirovic and

Conclusion

Introduction of the NVU concept has shifted the focus of research on neurovascular coupling and cerebral vascular diseases from neuron-centric views to the complex communication between elements of the NVU. With this new perspective, we now better appreciate how the activity-flow coupling in CNS works and that a successful neuroprotection is not feasible without microvascular protection. The ischemia/reperfusion-induced NVU injury, incomplete recirculation after recanalization and the role of

Acknowledgments

Dr. Turgay Dalkara׳s research is supported by The Turkish Academy of Sciences. Dr. Luis Alarcon-Martinez׳s research is supported by the Co-funded Brain Circulation Scheme of Marie Curie Actions into the 7th Framework Program of European Union. Dr. Luis Alarcon-Martinez prepared Fig. 3, Fig. 5.

References (163)

  • M. Kamouchi et al.

    Calcium influx pathways in rat CNS pericytes

    Brain Res. Mol. Brain Res.

    (2004)
  • M. Karow et al.

    Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells

    Cell Stem Cell

    (2012)
  • R.C. Koehler et al.

    Astrocytes and the regulation of cerebral blood flow

    Trends Neurosci.

    (2009)
  • F. Lauwers et al.

    Morphometry of the human cerebral cortex microcirculation: general characteristics and space-related profiles

    Neuroimage

    (2008)
  • K.R. Lees et al.

    Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials

    Lancet

    (2010)
  • F. Li et al.

    Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch

    Dev. Cell

    (2011)
  • J. Li et al.

    Nitric oxide and adenosine mediate vasodilation during functional activation in cerebellar cortex

    Neuropharmacology

    (1994)
  • N.J. Abbott et al.

    Astrocyte-endothelial interactions at the blood-brain barrier

    Nat. Rev. Neurosci.

    (2006)
  • T. Acker et al.

    Role of hypoxia in tumor angiogenesis-molecular and cellular angiogenic crosstalk

    Cell Tissue Res.

    (2003)
  • Al-Ali, F., Jefferson, A., Barrow, T., Cree, T., Louis, S., Luke, K., Major, K., Nemeth, D., Smoker, S., Walker, S.,...
  • A. Ames et al.

    Cerebral ischemia. II. The no-reflow phenomenon

    Am J. Pathol.

    (1968)
  • A. Armulik et al.

    Pericytes regulate the blood–brain barrier

    Nature

    (2010)
  • D.N. Atochin et al.

    Role of endothelial nitric oxide in cerebrovascular regulation

    Curr. Pharm. Biotechnol.

    (2011)
  • D. Attwell et al.

    Glial and neuronal control of brain blood flow

    Nature

    (2010)
  • T.L. Bailey et al.

    The nature and effects of cortical microvascular pathology in aging and Alzheimer׳s disease

    Neurol. Res.

    (2004)
  • H. Beck et al.

    Angiogenesis after cerebral ischemia

    Acta Neuropathol.

    (2009)
  • L. Belayev et al.

    Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses

    Stroke

    (2002)
  • R.D. Bell et al.

    Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer׳s disease

    Acta Neuropathol. (Berl.)

    (2009)
  • P. Blinder et al.

    Topological basis for the robust distribution of blood to rodent neocortex

    Proc. Natl. Acad. Sci. USA

    (2010)
  • F. Bosetti

    Arachidonic acid metabolism in brain physiology and pathology: lessons from genetically altered mouse models

    J. Neurochem.

    (2007)
  • W.R. Brown et al.

    Review: cerebral microvascular pathology in ageing and neurodegeneration

    Neuropathol. Appl. Neurobiol.

    (2011)
  • N. Calcinaghi et al.

    Metabotropic glutamate receptor mGluR5 is not involved in the early hemodynamic response

    J. Cereb. Blood Flow Metab.

    (2011)
  • T.F. Choudhri et al.

    Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation

    J. Clin. Investig.

    (1998)
  • A.H. Cornell-Bell et al.

    Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling

    Science

    (1990)
  • R.M. Crowell et al.

    Impaired microvascular filling after focal cerebral ischemia in the monkey. Modification by treatment

    Neurology

    (1972)
  • T. Dalkara et al.

    Can restoring incomplete microcirculatory reperfusion improve stroke outcome after thrombolysis?

    J. Cereb. Blood Flow Metab.

    (2012)
  • R. Daneman et al.

    Pericytes are required for blood–brain barrier integrity during embryogenesis

    Nature

    (2010)
  • J.C. De la Torre et al.

    Can disturbed brain microcirculation cause Alzheimer׳s disease?

    Neurol. Res.

    (1993)
  • G.J. Del Zoppo et al.

    Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons

    Stroke

    (1991)
  • G.J. Del Zoppo et al.

    Heterogeneity in the penumbra

    J. Cereb. Blood Flow Metab.

    (2011)
  • D.A. De Silva et al.

    Assessing reperfusion and recanalization as markers of clinical outcomes after intravenous thrombolysis in the echoplanar imaging thrombolytic evaluation trial (EPITHET)

    Stroke

    (2009)
  • L. Díaz-Flores et al.

    Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche

    Histol. Histopathol.

    (2009)
  • S. Dohgu et al.

    Brain pericytes increase the lipopolysaccharide-enhanced transcytosis of HIV-1 free virus across the in vitro blood–brain barrier: evidence for cytokine-mediated pericyte–endothelial cell crosstalk

    Fluids Barriers CNS

    (2013)
  • G.A. Donnan et al.

    How to make better use of thrombolytic therapy in acute ischemic stroke

    Nat. Rev. Neurol.

    (2011)
  • P. Dore-Duffy et al.

    CNS microvascular pericytes exhibit multipotential stem cell activity

    J. Cereb. Blood Flow Metab.

    (2006)
  • P. Dore-Duffy et al.

    Pericyte-mediated vasoconstriction underlies TBI-induced hypoperfusion

    Neurol. Res.

    (2011)
  • S. Duchemin et al.

    The complex contribution of NOS interneurons in the physiology of cerebrovascular regulation

    Front. Neural Circuits

    (2012)
  • S. Ejaz et al.

    Importance of pericytes and mechanisms of pericyte loss during diabetes retinopathy

    Diabetes Obes. Metab.

    (2008)
  • M. Enge et al.

    Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy

    EMBO J.

    (2002)
  • A. Ergul et al.

    Angiogenesis: a harmonized target for recovery after stroke

    Stroke J. Cereb. Circ.

    (2012)
  • Cited by (0)

    View full text