Pericytes are uniquely positioned within the neurovascular unit to serve as vital integrators, coordinators and effectors of many neurovascular functions, including angiogenesis, blood-brain barrier (BBB) formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow and clearance of toxic cellular byproducts necessary for proper CNS homeostasis and neuronal function. New studies have revealed that pericyte deficiency in the CNS leads to BBB breakdown and brain hypoperfusion resulting in secondary neurodegenerative changes. Here we review recent progress in understanding the biology of CNS pericytes and their role in health and disease.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Zlokovic, B.V. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 28, 202–208 (2005).
Tsai, P.S. et al. Correlations of neuronal and microvascular densities in murine cortex revealed by direct counting and colocalization of nuclei and vessels. J. Neurosci. 29, 14553–14570 (2009).
Moskowitz, M.A., Lo, E.H. & Iadecola, C. The science of stroke: mechanisms in search of treatments. Neuron 67, 181–198 (2010).
Zlokovic, B.V. New therapeutic targets in the neurovascular pathway in Alzheimer's disease. Neurotherapeutics 5, 409–414 (2008).
Zlokovic, B.V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008).
Weiss, N., Miller, F., Cazaubon, S. & Couraud, P.O. The blood-brain barrier in brain homeostasis and neurological diseases. Biochim. Biophys. Acta 1788, 842–857 (2009).
Armulik, A. et al. Pericytes regulate the blood-brain barrier. Nature 468, 557–561 (2010). This study demonstrates the role of pericytes in the maintenance of the blood-brain barrier and vascular density in vivo during adulthood.
Daneman, R., Zhou, L., Kebede, A.A. & Barres, B.A. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010). This study describes the role of pericytes in the formation of blood-brain barrier in vivo during embryonic development.
Bell, R.D. et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010). This study not only describes the role of pericytes in maintaining in vivo blood-brain barrier integrity, microvascular density and functional hyperemia during adulthood and brain aging but also shows that a primary loss of pericytes may lead to two parallel pathways of neurodegeneration, blood-brain barrier breakdown and hypoperfusion, which lead to secondary neurodegenerative changes.
Peppiatt, C.M., Howarth, C., Mobbs, P. & Attwell, D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700–704 (2006). This study demonstrates constriction of pericytes in response to chemical or electrical stimulation, suggesting that active neurons may directly send signals to pericytes to induce local blood flow changes.
Díaz-Flores, L. et al. Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol. Histopathol. 24, 909–969 (2009).
Stratman, A.N., Malotte, K.M., Mahan, R.D., Davis, M.J. & Davis, G.E. Pericyte recruitment during vasculogenic tube assembly stimulates endothelial basement membrane matrix formation. Blood 114, 5091–5101 (2009).
Gerhardt, H., Wolburg, H. & Redies, C. N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev. Dyn. 218, 472–479 (2000).
Li, F. et al. Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch. Dev. Cell 20, 291–302 (2011). This study shows the in vivo role of TGF-β and Notch signaling in the cooperative regulation of N-cadherin expression, pericyte-endothelial attachment and the prevention of perinatal hemorrhage.
Winkler, E.A., Bell, R.D. & Zlokovic, B.V. Lack of smad or notch leads to a fatal game of brain pericyte hopscotch. Dev. Cell 20, 279–280 (2011).
Bobbie, M.W., Roy, S., Trudeau, K., Munger, S.J. & Simon, A.M. Reduced connexin 43 expression and its effect on the development of vascular lesions in retinas of diabetic mice. Invest. Ophthalmol. Vis. Sci. 51, 3758–3763 (2010).
Chew, S.S., Johnson, C.S., Green, C.R. & Danesh-Meyer, H.V. Role of connexin43 in central nervous system injury. Exp. Neurol. 225, 250–261 (2010).
Shepro, D. & Morel, N.M. Pericyte physiology. FASEB J. 7, 1031–1038 (1993).
Bautch, V.L. & James, J.M. Neurovascular development: the beginning of a beautiful friendship. Cell Adh. Migr. 3, 199–204 (2009).
Etchevers, H.C., Vincent, C., Le Douarin, N.M. & Couly, G.F. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development 128, 1059–1068 (2001).
Korn, J., Christ, B. & Kurz, H. Neuroectodermal origin of brain pericytes and vascular smooth muscle cells. J. Comp. Neurol. 442, 78–88 (2002).
Kurz, H. Cell lineages and early patterns of embryonic CNS vascularization. Cell Adh. Migr. 3, 205–210 (2009).
Hellström, M., Kalen, M., Lindahl, P., Abramsson, A. & Betsholtz, C. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126, 3047–3055 (1999).
Abramsson, A. et al. Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development. Genes Dev. 21, 316–331 (2007).
Stenzel, D. et al. Peripheral mural cell recruitment requires cell-autonomous heparan sulfate. Blood 114, 915–924 (2009).
Ozerdem, U. & Stallcup, W.B. Early contribution of pericytes to angiogenic sprouting and tube formation. Angiogenesis 6, 241–249 (2003).
Ozerdem, U. & Stallcup, W.B. Pathological angiogenesis is reduced by targeting pericytes via the NG2 proteoglycan. Angiogenesis 7, 269–276 (2004).
Stratman, A.N., Schwindt, A.E., Malotte, K.M. & Davis, G.E. Endothelial-derived PDGF-BB and HB-EGF coordinately regulate pericyte recruitment during vasculogenic tube assembly and stabilization. Blood 116, 4720–4730 (2010).
Piquer-Gil, M., Garcia-Verdugo, J.M., Zipancic, I., Sanchez, M.J. & Alvarez-Dolado, M. Cell fusion contributes to pericyte formation after stroke. J. Cereb. Blood Flow Metab. 29, 480–485 (2009).
Lamagna, C. & Bergers, G. The bone marrow constitutes a reservoir of pericyte progenitors. J. Leukoc. Biol. 80, 677–681 (2006).
Kokovay, E., Li, L. & Cunningham, L.A. Angiogenic recruitment of pericytes from bone marrow after stroke. J. Cereb. Blood Flow Metab. 26, 545–555 (2006).
Gaengel, K., Genove, G., Armulik, A. & Betsholtz, C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 29, 630–638 (2009). Comprehensive review describing bidirectional endothelial cell–pericyte signal transduction.
Lindahl, P., Johansson, B.R., Leveen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997). Pioneering study using pericyte-deficient mice demonstrating microvascular instability and aneurysm formation in embryonic neural tube.
Tallquist, M.D., French, W.J. & Soriano, P. Additive effects of PDGF receptor beta signaling pathways in vascular smooth muscle cell development. PLoS Biol. 1, e52 (2003).
Levéen, P. et al. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 8, 1875–1887 (1994).
Soriano, P. Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev. 8, 1888–1896 (1994).
Lindblom, P. et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003).
Bjarnegård, M. et al. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 131, 1847–1857 (2004).
Enge, M. et al. Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J. 21, 4307–4316 (2002).
Andrae, J., Gallini, R. & Betsholtz, C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 22, 1276–1312 (2008).
Abramsson, A., Lindblom, P. & Betsholtz, C. Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J. Clin. Invest. 112, 1142–1151 (2003).
Winkler, E.A., Bell, R.D. & Zlokovic, B.V. Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling. Mol. Neurodegener. 5, 32 (2010).
Geraldes, P. et al. Activation of PKC-δ and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat. Med. 15, 1298–1306 (2009).
Sieczkiewicz, G.J. & Herman, I.M. TGF-beta 1 signaling controls retinal pericyte contractile protein expression. Microvasc. Res. 66, 190–196 (2003).
Lebrin, F., Deckers, M., Bertolino, P. & Ten Dijke, P. TGF-beta receptor function in the endothelium. Cardiovasc. Res. 65, 599–608 (2005).
Walshe, T.E. et al. TGF-beta is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature. PLoS ONE 4, e5149 (2009).
Braun, A. et al. Paucity of pericytes in germinal matrix vasculature of premature infants. J. Neurosci. 27, 12012–12024 (2007).
Vinukonda, G. et al. Effect of prenatal glucocorticoids on cerebral vasculature of the developing brain. Stroke 41, 1766–1773 (2010).
Carvalho, R.L.C. et al. Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice. J. Cell Sci. 120, 4269–4277 (2007).
Van Geest, R.J., Klaassen, I., Vogels, I.M., Van Noorden, C.J. & Schlingemann, R.O. Differential TGF-β signaling in retinal vascular cells: a role in diabetic retinopathy? Invest. Ophthalmol. Vis. Sci. 51, 1857–1865 (2010).
Paik, J.H. et al. Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev. 18, 2392–2403 (2004).
Goumans, M.J. et al. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 21, 1743–1753 (2002).
Dohgu, S. et al. Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production. Brain Res. 1038, 208–215 (2005).
Saunders, W.B. et al. Coregulation of vascular tube stabilization by endothelial cell TIMP-2 and pericyte TIMP-3. J. Cell Biol. 175, 179–191 (2006).
Saharinen, P. et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat. Cell Biol. 10, 527–537 (2008).
Wakui, S. et al. Localization of Ang-1, -2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis. Lab. Invest. 86, 1172–1184 (2006).
Jeansson, M. et al. Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J. Clin. Invest. 121, 2278–2289 (2011).
Hofmann, J.J. & Iruela-Arispe, M.L. Notch signaling in blood vessels: who is talking to whom about what? Circ. Res. 100, 1556–1568 (2007).
Liu, H., Kennard, S. & Lilly, B. NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ. Res. 104, 466–475 (2009).
Liu, H., Zhang, W., Kennard, S., Caldwell, R.B. & Lilly, B. Notch3 is critical for proper angiogenesis and mural cell investment. Circ. Res. 107, 860–870 (2010).
Regan, J.N. & Majesky, M.W. Building a vessel wall with notch signaling. Circ. Res. 104, 419–421 (2009).
Stewart, K.S., Zhou, Z., Zweidler-McKay, P. & Kleinerman, E.S. Delta-like ligand 4-Notch signaling regulates bone marrow-derived pericyte/vascular smooth muscle cell formation. Blood 117, 719–726 (2011).
Walshe, T.E. et al. Microvascular retinal endothelial and pericyte cell apoptosis in vitro: role of Hedgehog and Notch signaling. Invest. Ophthalmol. Vis. Sci. 52, 4472–4483 (2011).
Jin, S. et al. Notch signaling regulates platelet-derived growth factor receptor-β expression in vascular smooth muscle cells. Circ. Res. 102, 1483–1491 (2008).
Quaegebeur, A., Segura, I. & Carmeliet, P. Pericytes: blood-brain barrier safeguards against neurodegeneration? Neuron 68, 321–323 (2010).
Paul, J., Strickland, S. & Melchor, J.P. Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease. J. Exp. Med. 204, 1999–2008 (2007).
Chen, B., Cheng, Q., Yang, K. & Lyden, P.D. Thrombin mediates severe neurovascular injury during ischemia. Stroke 41, 2348–2352 (2010).
Mhatre, M. et al. Thrombin, a mediator of neurotoxicity and memory impairment. Neurobiol. Aging 25, 783–793 (2004).
Chen, Z.L. & Strickland, S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 91, 917–925 (1997).
Zhong, Z. et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat. Neurosci. 11, 420–422 (2008).
Zhong, Z. et al. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J. Clin. Invest. 119, 3437–3449 (2009).
Hellström, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543–553 (2001).
Ballabh, P. Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr. Res. 67, 1–8 (2010).
Virgintino, D. et al. An intimate interplay between precocious, migrating pericytes and endothelial cells governs human fetal brain angiogenesis. Angiogenesis 10, 35–45 (2007).
Candelario-Jalil, E., Yang, Y. & Rosenberg, G.A. Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 158, 983–994 (2009).
Dore-Duffy, P. et al. Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc. Res. 60, 55–69 (2000).
Darland, D.C. et al. Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival. Dev. Biol. 264, 275–288 (2003).
Gerhardt, H. & Betsholtz, C. Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. 314, 15–23 (2003).
Kamouchi, M. et al. Calcium influx pathways in rat CNS pericytes. Brain Res. Mol. Brain Res. 126, 114–120 (2004).
Hamilton, N.B., Attwell, D. & Hall, C.N. Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front. Neuroenergetics 2, 5 (2010).
Hirase, H., Creso, J., Singleton, M., Bartho, P. & Buzsaki, G. Two-photon imaging of brain pericytes in vivo using dextran-conjugated dyes. Glia 46, 95–100 (2004).
Chow, N. et al. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype. Proc. Natl. Acad. Sci. USA 104, 823–828 (2007).
Yemisci, M. et al. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat. Med. 15, 1031–1037 (2009).
Fernández-Klett, F., Offenhauser, N., Dirnagl, U., Priller, J. & Lindauer, U. Pericytes in capillaries are contractile in vivo, but arterioles mediate functional hyperemia in the mouse brain. Proc. Natl. Acad. Sci. USA 107, 22290–22295 (2010).
Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat. Rev. Neurosci. 5, 347–360 (2004).
Zachariah, M.A. & Cyster, J.G. Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science 328, 1129–1135 (2010).
Verbeek, M.M., Westphal, J.R., Ruiter, D.J. & de Waal, R.M. T lymphocyte adhesion to human brain pericytes is mediated via very late antigen-4/vascular cell adhesion molecule-1 interactions. J. Immunol. 154, 5876–5884 (1995).
Dore-Duffy, P., Katychev, A., Wang, X. & Van Buren, E. CNS microvascular pericytes exhibit multipotential stem cell activity. J. Cereb. Blood Flow Metab. 26, 613–624 (2006).
Hammes, H.P., Feng, Y., Pfister, F. & Brownlee, M. Diabetic retinopathy: targeting vasoregression. Diabetes 60, 9–16 (2011).
Gariano, R.F. & Gardner, T.W. Retinal angiogenesis in development and disease. Nature 438, 960–966 (2005).
Hammes, H.P. et al. Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes 53, 1104–1110 (2004).
Pfister, F. et al. Retinal overexpression of angiopoietin-2 mimics diabetic retinopathy and enhances vascular damages in hyperglycemia. Acta Diabetol. 47, 59–64 (2010).
Farkas, E. & Luiten, P.G. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog. Neurobiol. 64, 575–611 (2001).
Wu, Z. et al. Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nat. Med. 11, 959–965 (2005).
Vinters, H.V. et al. Microvasculature in brain biopsy specimens from patients with Alzheimer's disease: an immunohistochemical and ultrastructural study. Ultrastruct. Pathol. 18, 333–348 (1994).
Wisniewski, H.M., Wegiel, J., Wang, K.C. & Lach, B. Ultrastructural studies of the cells forming amyloid in the cortical vessel wall in Alzheimer's disease. Acta Neuropathol. 84, 117–127 (1992).
Wilhelmus, M.M. et al. Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells. Am. J. Pathol. 171, 1989–1999 (2007).
Iadecola, C. et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat. Neurosci. 2, 157–161 (1999).
Niwa, K. et al. Aβ1–40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc. Natl. Acad. Sci. USA 97, 9735–9740 (2000).
Bell, R.D. et al. SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells. Nat. Cell Biol. 11, 143–153 (2009).
The authors thank the US National Institutes of Health (grants R37 AG023084, R37 NS34467 and HL63290) and the Zilkha family for the research support.
The authors declare no competing financial interests.
About this article
Cite this article
Winkler, E., Bell, R. & Zlokovic, B. Central nervous system pericytes in health and disease. Nat Neurosci 14, 1398–1405 (2011). https://doi.org/10.1038/nn.2946
International Journal of Molecular Sciences (2020)
Journal of Neuroscience Methods (2020)
Neuroprotective Action of Teriflunomide in a Mouse Model of Transient Middle Cerebral Artery Occlusion
Elevated cerebrospinal fluid homocysteine is associated with blood-brain barrier disruption in amyotrophic lateral sclerosis patients
Neurological Sciences (2020)
Novel insights into astrocyte-mediated signaling of proliferation, invasion and tumor immune microenvironment in glioblastoma
Biomedicine & Pharmacotherapy (2020)