Interplay between Brain Pericytes and Endothelial Cells in Dementia
2021; Elsevier BV; Volume: 191; Issue: 11 Linguagem: Inglês
10.1016/j.ajpath.2021.07.003
ISSN1525-2191
AutoresTessa V. Procter, Anna Williams, Axel Montagne,
Tópico(s)Intracerebral and Subarachnoid Hemorrhage Research
ResumoPrevalence of dementia continues to increase because of the aging population and limited treatment options. Cerebral small vessel disease and Alzheimer disease are the two most common causes of dementia with vascular dysfunction being a large component of both their pathophysiologies. The neurogliovascular unit, in particular the blood-brain barrier (BBB), is required for maintaining brain homeostasis. A complex interaction exists among the endothelial cells, which line the blood vessels and pericytes, which surround them in the neurogliovascular unit. Disruption of the BBB in dementia precipitates cognitive decline. This review highlights how dysfunction of the endothelial-pericyte crosstalk contributes to dementia, and focuses on cerebral small vessel disease and Alzheimer disease. It also examines loss of pericyte coverage and subsequent downstream changes. Furthermore, it examines how disruption of the intimate crosstalk between endothelial cells and pericytes leads to alterations in cerebral blood flow, transcription, neuroinflammation, and transcytosis, contributing to breakdown of the BBB. Finally, this review illustrates how cumulation of loss of endothelial-pericyte crosstalk is a major driving force in dementia pathology. Prevalence of dementia continues to increase because of the aging population and limited treatment options. Cerebral small vessel disease and Alzheimer disease are the two most common causes of dementia with vascular dysfunction being a large component of both their pathophysiologies. The neurogliovascular unit, in particular the blood-brain barrier (BBB), is required for maintaining brain homeostasis. A complex interaction exists among the endothelial cells, which line the blood vessels and pericytes, which surround them in the neurogliovascular unit. Disruption of the BBB in dementia precipitates cognitive decline. This review highlights how dysfunction of the endothelial-pericyte crosstalk contributes to dementia, and focuses on cerebral small vessel disease and Alzheimer disease. It also examines loss of pericyte coverage and subsequent downstream changes. Furthermore, it examines how disruption of the intimate crosstalk between endothelial cells and pericytes leads to alterations in cerebral blood flow, transcription, neuroinflammation, and transcytosis, contributing to breakdown of the BBB. Finally, this review illustrates how cumulation of loss of endothelial-pericyte crosstalk is a major driving force in dementia pathology. Dementia is characterized by a gradual cognitive impairment with additional symptoms, such as depression and changes to balance and gait.1Wardlaw J. Smith C. Dichgans M. 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Prevention of vascular cognitive impairment.Stroke. 2012; 43: 3137-3146Crossref PubMed Scopus (57) Google Scholar suggesting that vascular dysfunction is a major contributing factor in both. Vascular dysfunction can take many forms that involve many cells comprising the neurogliovascular unit (NVU) and include disruption of the blood-brain barrier (BBB), which plays a vital role in maintaining cerebral homeostasis. However, this review focuses on how the complex interactions between endothelial cells lining the blood vessels and pericytes closely apposed to the endothelial cells on the abluminal side contribute to BBB disruption, a central pathologic mechanism in these two important dementias. Blood vessels throughout the body are normally partly permeable to allow the exchange of nutrients, solutes, and chemical signals between tissue and the blood, which are vital for keeping cells alive. However, the brain microenvironment is different from the rest of the body and requires tighter control provided by the BBB. Substance movement can occur paracellularly (between endothelial cells) or transcellularly (across endothelial cells), and the BBB tightly regulates the two types of substance movement via junctional complexes between endothelial cells and through expression of membrane receptors and pumps, with limited passive diffusion.6Abbott N.J. Patabendige A.A. Dolman D.E. Yusof S.R. Begley D.J. Structure and function of the blood-brain barrier.Neurobiol Dis. 2010; 37: 13-25Crossref PubMed Scopus (2595) Google Scholar Furthermore, the BBB allows separation of peripheral and central neurotransmitters, avoiding potential cross-signaling.6Abbott N.J. Patabendige A.A. Dolman D.E. Yusof S.R. Begley D.J. Structure and function of the blood-brain barrier.Neurobiol Dis. 2010; 37: 13-25Crossref PubMed Scopus (2595) Google Scholar Pathogens, plasma proteins, and immune cells from the blood can have severe detrimental consequences if present within the brain, and disruption to the BBB is a major component of many neurologic diseases, including AD and cSVD.7Rosenberg G.A. Neurological diseases in relation to the blood-brain barrier.J Cereb Blood Flow Metab. 2012; 32: 1139-1151Crossref PubMed Scopus (277) Google Scholar The BBB comprises various components, commonly referred to as the NVU (Figure 1), including endothelial cells, pericytes, basement membrane, astrocyte end-feet, and surrounding oligodendrocytes and microglia, and links to neurons in a process called neurovascular coupling in which increased neuronal activity leads to increased blood flow to that area.6Abbott N.J. Patabendige A.A. Dolman D.E. Yusof S.R. Begley D.J. Structure and function of the blood-brain barrier.Neurobiol Dis. 2010; 37: 13-25Crossref PubMed Scopus (2595) Google Scholar The NVU is unique in that its cellular components are in close and sometimes direct contact with one another, allowing for intimate crosstalk.6Abbott N.J. Patabendige A.A. Dolman D.E. Yusof S.R. Begley D.J. Structure and function of the blood-brain barrier.Neurobiol Dis. 2010; 37: 13-25Crossref PubMed Scopus (2595) Google Scholar Endothelial cells line the blood vessels, and pericytes are mesenchymal-derived cells on the brain side of endothelial cells. Pericytes are found encircling capillaries as well as precapillary arterioles and postcapillary venules, whereas vascular smooth muscle cells (VSMCs) are found in larger vessels.8Armulik A. Abramsson A. Betsholtz C. Endothelial/pericyte interactions.Circ Res. 2005; 97: 512-523Crossref PubMed Scopus (1416) Google Scholar Collectively, pericytes and VSMCs are known as vascular mural cells (VMCs). In human tissue, pericytes form two subtypes with enriched gene expression of either transmembrane transporters or extracellular matrix (ECM) regulation genes.9Yang A.C. Vest R.T. Kern F. Lee D. Maat C.A. Losada P.M. Chen M.B. Agam M. Schaum N. Khoury N. Calcuttawala K. Palovics R. Shin A. Wang E.Y. Luo J. Gate D. Siegenthaler J.A. McNerney M.W. Keller A. Wyss-Coray T. A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk.bioRxiv. 2021; ([Preprint] doi:10.1101/2021.04.26.441262)Google Scholar In addition, pericyte morphology plays an important role in maintaining BBB integrity because pericytes in the median eminence (ME), where BBB leakage naturally occurs, have a more irregular shape and less prominent nucleus compared with cortical tissue with a functional BBB.10Pfau S.J. Langen U.H. Fisher T.M. Prakash I. Nagpurwala F. Lozoya R.A. Lee W.-C.A. Wu Z. Gu C. Vascular and perivascular cell profiling reveals the molecular and cellular bases of blood-brain barrier heterogeneity.bioRxiv. 2021; ([Preprint] doi:10.1101/2021.04.26.441465)PubMed Google Scholar A study of pericytes in the mouse cortex found that, depending on their location along the vascular tree, pericytes have different phenotypes.11Grant R. Hartmann D. Underly R. Berthiaume A. Bhat N. Shih A. Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex.J Cereb Blood Flow Metab. 2019; 39: 411-425Crossref PubMed Scopus (77) Google Scholar Grant et al11Grant R. Hartmann D. Underly R. Berthiaume A. Bhat N. Shih A. Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex.J Cereb Blood Flow Metab. 2019; 39: 411-425Crossref PubMed Scopus (77) Google Scholar subdivided pericytes into ensheathing pericytes located on larger diameter precapillary arterioles with shorter cell lengths and α-smooth muscle actin (α-SMA), and mesh pericytes and thin-strand pericytes located on smaller diameter capillaries with longer cell lengths, and no detectable α-SMA. They argue that ensheathing pericytes are transitional mural cells with characteristics of both VSMCs and pericytes, whereas mesh and thin-strand pericytes comprise the capillary pericytes.11Grant R. Hartmann D. Underly R. Berthiaume A. Bhat N. Shih A. Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex.J Cereb Blood Flow Metab. 2019; 39: 411-425Crossref PubMed Scopus (77) Google Scholar Despite a morphologic continuum in mice, there appears to be a more distinct difference in gene expression between VSMCs and pericytes in humans.9Yang A.C. Vest R.T. Kern F. Lee D. Maat C.A. Losada P.M. Chen M.B. Agam M. Schaum N. Khoury N. Calcuttawala K. Palovics R. Shin A. Wang E.Y. Luo J. Gate D. Siegenthaler J.A. McNerney M.W. Keller A. Wyss-Coray T. A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk.bioRxiv. 2021; ([Preprint] doi:10.1101/2021.04.26.441262)Google Scholar Much of the literature makes no distinctions between pericyte subtypes because of not assessing morphologic differences. Furthermore, platelet-derived growth factor receptor β (PDGFR-β), which is expressed in all pericyte subtypes,11Grant R. Hartmann D. Underly R. Berthiaume A. Bhat N. Shih A. Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex.J Cereb Blood Flow Metab. 2019; 39: 411-425Crossref PubMed Scopus (77) Google Scholar is frequently used as a pericyte marker. However, other CNS cell types have also been found to express PDGFR-β, such as perivascular fibroblast–like cells12Vanlandewijck M. He L. Mäe M.A. Andrae J. Ando K. Del Gaudio F. Nahar K. Lebouvier T. Laviña B. Gouveia L. Sun Y. Raschperger E. Räsänen M. Zarb Y. Mochizuki N. Keller A. Lendahl U. Betsholtz C. A molecular atlas of cell types and zonation in the brain vasculature.Nature. 2018; 554: 475-480Crossref PubMed Scopus (518) Google Scholar which adds further complexity to distinguishing different pericytes subtypes and from surrounding perivascular cells. 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Cellular mechanisms of CNS pericytes.Brain Res Bull. 2000; 51: 363-369Crossref PubMed Scopus (140) Google Scholar It is the endothelial cells of the NVU that are the mainstay of the BBB, and together the other components of the NVU help regulate it.6Abbott N.J. Patabendige A.A. Dolman D.E. Yusof S.R. Begley D.J. Structure and function of the blood-brain barrier.Neurobiol Dis. 2010; 37: 13-25Crossref PubMed Scopus (2595) Google Scholar Endothelial cells of the BBB possess unique properties reflected in their specialized gene expression profile.10Pfau S.J. Langen U.H. Fisher T.M. Prakash I. Nagpurwala F. Lozoya R.A. Lee W.-C.A. Wu Z. Gu C. Vascular and perivascular cell profiling reveals the molecular and cellular bases of blood-brain barrier heterogeneity.bioRxiv. 2021; ([Preprint] doi:10.1101/2021.04.26.441465)PubMed Google Scholar It is their junctional proteins in particular that confer the barrier's characteristic properties of limiting paracellular permeability. 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