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Acta Neuropathologica May 2020Pericyte loss and deficient vascular platelet-derived growth factor receptor-β (PDGFRβ) signaling are prominent features of the blood-brain barrier breakdown described...
Pericyte loss and deficient vascular platelet-derived growth factor receptor-β (PDGFRβ) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid β-protein (Aβ) deposits in retinas of AD patients. However, the cellular and molecular mechanisms of such retinal vascular pathology were not previously explored. Here, by modifying a method of enzymatically clearing non-vascular retinal tissue and fluorescent immunolabeling of the isolated blood vessel network, we identified substantial pericyte loss together with significant Aβ deposition in retinal microvasculature and pericytes in AD. Evaluation of postmortem retinas from a cohort of 56 human donors revealed an early and progressive decrease in vascular PDGFRβ in mild cognitive impairment (MCI) and AD compared to cognitively normal controls. Retinal PDGFRβ loss significantly associated with increased retinal vascular Aβ and Aβ burden. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were also detected. Mapping of PDGFRβ and Aβ levels in pre-defined retinal subregions indicated that certain geometrical and cellular layers are more susceptible to AD pathology. Further, correlations were identified between retinal vascular abnormalities and cerebral Aβ burden, cerebral amyloid angiopathy (CAA), and clinical status. Overall, the identification of pericyte and PDGFRβ loss accompanying increased vascular amyloidosis in Alzheimer's retina implies compromised blood-retinal barrier integrity and provides new targets for AD diagnosis and therapy.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Blood-Brain Barrier; Brain; Cerebral Amyloid Angiopathy; Cognition; Female; Humans; Male; Pericytes; Retina
PubMed: 32043162
DOI: 10.1007/s00401-020-02134-w -
Nature Neuroscience Jul 2019Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in...
Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.
Topics: Animals; Brain Ischemia; Capillaries; Carrier Proteins; Cells, Cultured; Cerebrovascular Circulation; Cytokines; Endothelial Cells; Female; Genes, Reporter; Infusions, Intraventricular; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Nerve Degeneration; Nerve Tissue Proteins; Neuroglia; Neurons; Neurotoxins; Pericytes; Promoter Regions, Genetic; Recombinant Fusion Proteins; Shock
PubMed: 31235908
DOI: 10.1038/s41593-019-0434-z -
Cells Jul 2023Pericytes are specialized cells located in close proximity to endothelial cells within the microvasculature. They play a crucial role in regulating blood flow,... (Review)
Review
Pericytes are specialized cells located in close proximity to endothelial cells within the microvasculature. They play a crucial role in regulating blood flow, stabilizing vessel walls, and maintaining the integrity of the blood-brain barrier. The loss of pericytes has been associated with the development and progression of various diseases, such as diabetes, Alzheimer's disease, sepsis, stroke, and traumatic brain injury. This review examines the detection of pericyte loss in different diseases, explores the methods employed to assess pericyte coverage, and elucidates the potential mechanisms contributing to pericyte loss in these pathological conditions. Additionally, current therapeutic strategies targeting pericytes are discussed, along with potential future interventions aimed at preserving pericyte function and promoting disease mitigation.
Topics: Humans; Pericytes; Endothelial Cells; Blood-Brain Barrier; Stroke; Brain Injuries, Traumatic
PubMed: 37566011
DOI: 10.3390/cells12151931 -
The Journal of Clinical Investigation Jul 2020Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Vascular pericyte degeneration is the predominant clinical manifestation of DR, yet...
Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Vascular pericyte degeneration is the predominant clinical manifestation of DR, yet the mechanism governing pericyte degeneration is poorly understood. Circular RNAs (circRNAs) play important roles in multiple biological processes and disease progression. Here, we investigated the role of circRNA in pericyte biology and diabetes-induced retinal vascular dysfunction. cZNF532 expression was upregulated in pericytes under diabetic stress, in the retinal vessels of a diabetic murine model, and in the vitreous humor of diabetic patients. cZNF532 silencing reduced the viability, proliferation, and differentiation of pericytes and suppressed the recruitment of pericytes toward endothelial cells in vitro. cZNF532 regulated pericyte biology by acting as a miR-29a-3p sponge and inducing increased expression of NG2, LOXL2, and CDK2. Knockdown of cZNF532 or overexpression of miR-29a-3p aggravated streptozotocin-induced retinal pericyte degeneration and vascular dysfunction. By contrast, overexpression of cZNF532 or inhibition of miR-29a-3p ameliorated human diabetic vitreous-induced retinal pericyte degeneration and vascular dysfunction. Collectively, these data identify a circRNA-mediated mechanism that coordinates pericyte biology and vascular homeostasis in DR. Induction of cZNF532 or antagonism of miR-29a-3p is an exploitable therapeutic approach for the treatment of DR.
Topics: Animals; Cell Line; Diabetic Retinopathy; Eye Proteins; Humans; Mice; MicroRNAs; Pericytes; RNA, Circular; Retinal Vessels
PubMed: 32343678
DOI: 10.1172/JCI123353 -
JCI Insight May 2022Molecular signaling in the tumor microenvironment (TME) is complex, and crosstalk among various cell compartments in supporting metastasis remains poorly understood. In...
Molecular signaling in the tumor microenvironment (TME) is complex, and crosstalk among various cell compartments in supporting metastasis remains poorly understood. In particular, the role of vascular pericytes, a critical cellular component in the TME, in cancer invasion and metastasis warrants further investigation. Here, we report that an elevation of FGF-2 signaling in samples from patients with nasopharyngeal carcinoma (NPC) and xenograft mouse models promoted NPC metastasis. Mechanistically, tumor cell-derived FGF-2 strongly promoted pericyte proliferation and pericyte-specific expression of an orphan chemokine (C-X-C motif) ligand 14 (CXCL14) via FGFR1/AHR signaling. Gain- and loss-of-function experiments validated that pericyte-derived CXCL14 promoted macrophage recruitment and polarization toward an M2-like phenotype. Genetic knockdown of FGF2 or genetic depletion of tumoral pericytes blocked CXCL14 expression and tumor-associated macrophage (TAM) infiltration. Pharmacological inhibition of TAMs by clodronate liposome treatment resulted in a reduction of FGF-2-induced pulmonary metastasis. Together, these findings shed light on the inflammatory role of tumoral pericytes in promoting TAM-mediated metastasis. We provide mechanistic insight into an FGF-2/FGFR1/pericyte/CXCL14/TAM stromal communication axis in NPC and propose an effective antimetastasis therapy concept by targeting a pericyte-derived inflammation for NPC or FGF-2hi tumors.
Topics: Animals; Cell Line, Tumor; Fibroblast Growth Factor 2; Humans; Macrophages; Mice; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Pericytes; Tumor Microenvironment
PubMed: 35439170
DOI: 10.1172/jci.insight.157874 -
American Journal of Physiology. Lung... Jul 2023Pericytes are microvascular mural cells that directly contact endothelial cells. They have long been recognized for their roles in vascular development and homeostasis,... (Review)
Review
Pericytes are microvascular mural cells that directly contact endothelial cells. They have long been recognized for their roles in vascular development and homeostasis, but more recently have been identified as key mediators of the host response to injury. In this context, pericytes possess a surprising degree of cellular plasticity, behaving dynamically when activated and potentially participating in a range of divergent host responses to injury. Although there has been much interest in the role of pericytes in fibrosis and tissue repair, their involvement in the initial inflammatory process has been understudied and is increasingly appreciated. Pericytes mediate inflammation through leukocyte trafficking and cytokine signaling, respond to pathogen-associated molecular patterns and tissue damage-associated molecular patterns, and may drive vascular inflammation during human SARS-CoV-2 infection. In this review, we highlight the inflammatory phenotype of activated pericytes during organ injury, with an emphasis on novel findings relevant to pulmonary pathophysiology.
Topics: Humans; Pericytes; Endothelial Cells; COVID-19; SARS-CoV-2; Lung; Inflammation; Inflammation Mediators
PubMed: 37130806
DOI: 10.1152/ajplung.00354.2022 -
British Journal of Cancer Jun 2022A recent perspective on vessel co-option and angiotropic extravascular migratory metastasis by Lugassy et al. suggests cancers use both mechanisms sequentially during...
A recent perspective on vessel co-option and angiotropic extravascular migratory metastasis by Lugassy et al. suggests cancers use both mechanisms sequentially during tumour growth and spread.
Topics: Cell Movement; Humans; Neoplasms; Pericytes
PubMed: 35352021
DOI: 10.1038/s41416-022-01795-6 -
The Journal of Clinical Investigation May 2022Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly...
Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca2+ concentration ([Ca2+]i) in pericytes activated chloride efflux through the Ca2+-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplified the pericyte [Ca2+]i rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slowed the ischemia-evoked pericyte [Ca2+]i rise, capillary constriction, and pericyte death; reduced neutrophil stalling; and improved cerebrovascular reperfusion. Genetic analysis implicated altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimer's disease and vascular dementia.
Topics: Calcium; Cerebrovascular Circulation; Humans; Ischemia; Pericytes; Stroke
PubMed: 35316222
DOI: 10.1172/JCI154118 -
Stroke Jul 2021The article summarizes recent studies investigating mechanisms of collateral flow variability in stroke, and the role of pericytes in cerebral microcirculation and... (Review)
Review
The article summarizes recent studies investigating mechanisms of collateral flow variability in stroke, and the role of pericytes in cerebral microcirculation and stroke.
Topics: Animals; Cerebral Small Vessel Diseases; Collateral Circulation; Humans; Pericytes
PubMed: 34078110
DOI: 10.1161/STROKEAHA.121.033556 -
Angiogenesis Nov 2021Pericytes play essential roles in blood-brain barrier integrity and their dysfunction is implicated in neurological disorders such as stroke although the underlying...
Pericytes play essential roles in blood-brain barrier integrity and their dysfunction is implicated in neurological disorders such as stroke although the underlying mechanisms remain unknown. Hypoxia-inducible factor-1 (HIF-1), a master regulator of injury responses, has divergent roles in different cells especially during stress scenarios. On one hand HIF-1 is neuroprotective but on the other it induces vascular permeability. Since pericytes are critical for barrier stability, we asked if pericyte HIF-1 signaling impacts barrier integrity and injury severity in a mouse model of ischemic stroke. We show that pericyte HIF-1 loss of function (LoF) diminishes ischemic damage and barrier permeability at 3 days reperfusion. HIF-1 deficiency preserved barrier integrity by reducing pericyte death thereby maintaining vessel coverage and junctional protein organization, and suppressing vascular remodeling. Importantly, considerable improvements in sensorimotor function were observed in HIF-1 LoF mice indicating that better vascular functionality post stroke improves outcome. Thus, boosting vascular integrity by inhibiting pericytic HIF-1 activation and/or increasing pericyte survival may be a lucrative option to accelerate recovery after severe brain injury.
Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Ischemic Stroke; Mice; Pericytes; Stroke
PubMed: 34046769
DOI: 10.1007/s10456-021-09796-4