RESUMEN
Diabetic retinopathy is a common yet severe complication of diabetes mellitus and is the leading cause of blindness in middle-aged adults. After years of poorly managed hyperglycemia, complications begin as non-proliferative diabetic retinopathy but can then progress into the proliferative stage marked by neovascularization of the retina. Multiple pathologic mechanisms caused by chronic hyperglycemia damage the retinal vasculature leading to pericyte drop out and the progression of the disease. This review outlines the major pathways of pathogenesis in diabetic retinopathy, highlighting the protective role pericytes play in preserving the blood-retinal barrier. Given the loss of this cell line is a defining feature of the disease, ways in which to prevent pericyte dropout within retinal vasculature is discussed, targeting various pathogenesis pathways of diabetic retinopathy.
Asunto(s)
Barrera Hematorretinal , Retinopatía Diabética , Pericitos , Retinopatía Diabética/patología , Retinopatía Diabética/metabolismo , Pericitos/metabolismo , Pericitos/patología , Humanos , Barrera Hematorretinal/metabolismo , Animales , Vasos Retinianos/patología , Vasos Retinianos/metabolismoRESUMEN
Alzheimer's disease (AD) is the most common cause of dementia, characterized by memory loss, cognitive decline, personality changes, and various neurological symptoms. The role of blood-brain barrier (BBB) injury, extracellular matrix (ECM) abnormalities, and oligodendrocytes (ODCs) dysfunction in AD has gained increasing attention, yet the detailed pathogenesis remains elusive. This study integrates single-cell sequencing of AD patients' cerebrovascular system with a genome-wide association analysis. It aims to elucidate the associations and potential mechanisms behind pericytes injury, ECM disorder, and ODCs dysfunction in AD pathogenesis. Finally, we identified that abnormalities in the pericyte PI3K-AKT-FOXO signaling pathway may be involved in the pathogenic process of AD. This comprehensive approach sheds new light on the complex etiology of AD and opens avenues for advanced research into its pathogenesis and therapeutic strategies.
Asunto(s)
Enfermedad de Alzheimer , Barrera Hematoencefálica , Estudio de Asociación del Genoma Completo , Pericitos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/etiología , Humanos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Pericitos/patología , Pericitos/metabolismo , Transducción de Señal , Oligodendroglía/metabolismo , Oligodendroglía/patología , Matriz Extracelular/metabolismo , Microvasos/patología , Microvasos/metabolismo , Análisis de la Célula Individual , Femenino , Masculino , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
BACKGROUND: TGF (transforming growth factor)-ß pathway is central to blood-brain barrier development as it regulates cross talk between pericytes and endothelial cells. Murine embryos lacking TGFß receptor Alk5 (activin receptor-like kinase 5) in brain pericytes (mutants) display endothelial cell hyperproliferation, abnormal vessel morphology, and gross germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH), leading to perinatal lethality. Mechanisms underlying how ALK5 signaling in pericytes noncell autonomously regulates endothelial cell behavior remain elusive. METHODS: Transcriptomic analysis of human brain pericytes with ALK5 silencing identified differential gene expression. Brain vascular cells isolated from mutant embryonic mice with GMH-IVH and preterm human IVH brain samples were utilized for target validation. Finally, pharmacological and genetic inhibition was used to study the therapeutic effects on GMH-IVH pathology. RESULTS: Herein, we establish that the TGFß/ALK5 pathway robustly represses ANGPT2 (angiopoietin-2) in pericytes via epigenetic remodeling. TGFß-driven SMAD (suppressor of mothers against decapentaplegic) 3/4 associates with TGIF1 (TGFß-induced factor homeobox 1) and HDAC (histone deacetylase) 5 to form a corepressor complex at the Angpt2 promoter, resulting in promoter deacetylation and gene repression. Moreover, murine and human germinal matrix vessels display increased ANGPT2 expression during GMH-IVH. Isolation of vascular cells from murine germinal matrix identifies pericytes as a cellular source of excessive ANGPT2. In addition, mutant endothelial cells exhibit higher phosphorylated TIE2 (tyrosine protein kinase receptor). Pharmacological or genetic inhibition of ANGPT2 in mutants improves germinal matrix vessel morphology and attenuates GMH pathogenesis. Importantly, genetic ablation of Angpt2 in mutant pericytes prevents perinatal lethality, prolonging survival. CONCLUSIONS: This study demonstrates that TGFß-mediated ANGPT2 repression in pericytes is critical for maintaining blood-brain barrier integrity and identifies pericyte-derived ANGPT2 as an important pathological target for GMH-IVH.
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Angiopoyetina 2 , Pericitos , Factor de Crecimiento Transformador beta , Pericitos/metabolismo , Pericitos/patología , Animales , Ratones , Humanos , Angiopoyetina 2/metabolismo , Angiopoyetina 2/genética , Factor de Crecimiento Transformador beta/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patología , Hemorragia Cerebral/genética , Transducción de Señal/fisiología , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/genética , Células Endoteliales/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
Diabetes mediates endothelial dysfunction and increases the risk of Alzheimer's disease and related dementias. Diabetes also dysregulates the ET system. ET-1-mediated constriction of brain microvascular pericytes (BMVPCs) has been shown to contribute to brain hypoperfusion. Cellular senescence, a process that arrests the proliferation of harmful cells and instigates phenotypical changes and proinflammatory responses in endothelial cells that impact their survival and function. Thus, we hypothesized that ET-1 mediates BMVPC senescence and phenotypical changes in diabetes-like conditions. Human BMVPCs were incubated in diabetes-like conditions with or without ET-1 (1 µmol/L) for 3 and 7 days. Hydrogen peroxide (100 µmol/L H2O2) was used as a positive control for senescence and to mimic ischemic conditions. Cells were stained for senescence-associated ß-galactosidase or processed for immunoblotting and quantitative real-time PCR analyses. In additional experiments, cells were stimulated with ET-1 in the presence or absence of ETA receptor antagonist BQ-123 (20 µmol/L) or ETB receptor antagonist BQ-788 (20 µmol/L). ET-1 stimulation increased ß-galactosidase accumulation which was prevented by BQ-123. ET-1 also increased traditional senescence marker p16 protein and pericyte-specific senescence markers, TGFB1i1, PP1CA, and IGFBP7. Furthermore, ET-1 stimulated contractile protein α-SMA and microglial marker ostepontin in high glucose suggesting a shift toward an ensheathing or microglia-like phenotype. In conclusion, ET-1 triggers senescence, alters ETA and ETB receptors, and causes phenotypical changes in BMVPCs under diabetes-like conditions. These in vitro findings need to be further studied in vivo to establish the role of ETA receptors in the progression of pericyte senescence and phenotypical changes in VCID.
Asunto(s)
Encéfalo , Senescencia Celular , Endotelina-1 , Pericitos , Receptor de Endotelina A , Humanos , Encéfalo/metabolismo , Encéfalo/patología , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Diabetes Mellitus/metabolismo , Endotelina-1/metabolismo , Endotelina-1/farmacología , Pericitos/metabolismo , Pericitos/efectos de los fármacos , Pericitos/patología , Fenotipo , Receptor de Endotelina A/metabolismo , Receptor de Endotelina A/genéticaRESUMEN
Traumatic brain injury impairs brain function through various mechanisms. Recent studies have shown that alterations in pericytes in various diseases affect neurovascular function, but the effects of TBI on hippocampal pericytes remain unclear. Here, we investigated the effects of RAGE activation on pericytes after TBI using male C57BL/6 J mice. Hippocampal samples were collected at different time points within 7 days after TBI, the expression of PDGFR-ß, NG2 and the HMGB1-S100B/RAGE signaling pathway was assessed by Western blotting, and the integrity of the hippocampal BBB at different time points was measured by immunofluorescence. RAGE-associated BBB damage in hippocampal pericytes occurred early after cortical impact. By culturing primary mouse brain microvascular pericytes, we determined the different effects of HMGB1-S100B on pericyte RAGE. To investigate whether RAGE blockade could protect neurological function after TBI, we reproduced the process of CCI by administering FPS-ZM1 to RAGE-/- mice. TEM images and BBB damage-related assays showed that inhibition of RAGE resulted in a significant improvement in the number of hippocampal vascular basement membranes and tight junctions and a reduction in perivascular oedema compared with those in the untreated group. In contrast, mouse behavioural testing and doublecortin staining indicated that targeting the HMGB1-S100B/RAGE axis after CCI could protect neurological function by reducing pericyte-associated BBB damage. In conclusion, the present study provides experimental evidence for the strong correlation between the pericyte HMGB1-S100B/RAGE axis and NVU damage in the hippocampus at the early stage of TBI and further demonstrates that pericyte RAGE serves as an important target for the protection of neurological function after TBI.
Asunto(s)
Barrera Hematoencefálica , Lesiones Traumáticas del Encéfalo , Hipocampo , Ratones Endogámicos C57BL , Pericitos , Receptor para Productos Finales de Glicación Avanzada , Animales , Pericitos/metabolismo , Pericitos/patología , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/metabolismo , Ratones , Masculino , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/metabolismo , Ratones Noqueados , Proteína HMGB1/metabolismo , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , BenzamidasRESUMEN
Diabetic retinopathy (DR) is the leading cause of vision loss and blindness among working-age adults. Pericyte loss is an early pathological feature of DR. Under hyperglycemic conditions, reactive oxygen species (ROS) production increases, leading to oxidative stress and subsequent mitochondrial dysfunction and apoptosis. Dysfunctional pericyte can cause retinal vascular leakage, obliteration, and neovascularization. Glutaredoxin 2 (Grx2) is a mitochondrial glutathione-dependent oxidoreductase which protects cells against oxidative insults by safeguarding mitochondrial function. Whether Grx2 plays a protective role in diabetes-induced microvascular dysfunction remains unclear. Our findings revealed that diabetes-related stress reduced Grx2 expression in pericytes, but not in endothelial cells. Grx2 knock-in ameliorated diabetes-induced microvascular dysfunction in vivo DR models. Decreased Grx2 expression led to significant pericyte apoptosis, and pericyte dysfunction, namely reduced pericyte recruitment towards endothelial cells and increased endothelial cell permeability. Conversely, upregulating Grx2 reversed these effects. Furthermore, Grx2 regulated pericyte apoptosis by modulating complex I activity, which is crucial for pericyte mitochondrial function. Overall, our study uncovered a novel mechanism whereby high glucose inhibited Grx2 expression in vivo and in vitro. Grx2 downregulation exacerbated pericyte apoptosis, pericyte dysfunction, and retinal vascular dysfunction by inactivating complex I and mediating mitochondrial dysfunction in pericytes.
Asunto(s)
Apoptosis , Diabetes Mellitus Experimental , Retinopatía Diabética , Regulación hacia Abajo , Glutarredoxinas , Pericitos , Vasos Retinianos , Pericitos/metabolismo , Pericitos/patología , Animales , Glutarredoxinas/metabolismo , Glutarredoxinas/genética , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Vasos Retinianos/patología , Vasos Retinianos/metabolismo , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Masculino , Células Cultivadas , Permeabilidad Capilar , Western BlottingRESUMEN
OBJECTIVES: Diabetes is closely linked to hearing loss, yet the exact mechanisms remain unclear. Cochlear stria vascularis and pericytes (PCs) are crucial for hearing. This study investigates whether high glucose induces apoptosis in the cochlear stria vascularis and pericytes via elevated ROS levels due to oxidative stress, impacting hearing loss. METHODS: We established a type II diabetes model in C57BL/6J mice and used auditory brainstem response (ABR), Evans blue staining, HE staining, immunohistochemistry, and immunofluorescence to observe changes in hearing, blood-labyrinth barrier (BLB) permeability, stria vascularis morphology, and apoptosis protein expression. Primary cultured stria vascularis pericytes were subjected to high glucose, and apoptosis levels were assessed using flow cytometry, Annexin V-FITC, Hoechst 33342 staining, Western blot, Mitosox, and JC-1 probes. RESULTS: Diabetic mice showed decreased hearing thresholds, reduced stria vascularis density, increased oxidative stress, cell apoptosis, and decreased antioxidant levels. High glucose exposure increased apoptosis and ROS content in pericytes, while mitochondrial membrane potential decreased, with AIF and cytochrome C (CytC) released from mitochondria to the cytoplasm. Adding oxidative scavengers reduced AIF and CytC release, decreasing pericyte apoptosis. DISCUSSION: Hyperglycemia may induce mitochondrial apoptosis of cochlear stria vascularis pericytes through oxidative stress.
Asunto(s)
Factor Inductor de la Apoptosis , Apoptosis , Citocromos c , Hiperglucemia , Ratones Endogámicos C57BL , Mitocondrias , Estrés Oxidativo , Pericitos , Proteínas Proto-Oncogénicas c-bcl-2 , Especies Reactivas de Oxígeno , Estría Vascular , Animales , Pericitos/metabolismo , Pericitos/efectos de los fármacos , Pericitos/patología , Estría Vascular/metabolismo , Estría Vascular/patología , Ratones , Especies Reactivas de Oxígeno/metabolismo , Mitocondrias/metabolismo , Citocromos c/metabolismo , Factor Inductor de la Apoptosis/metabolismo , Hiperglucemia/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Masculino , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Cóclea/metabolismo , Cóclea/patologíaRESUMEN
The combination of lineage tracing and immunohistochemistry has helped to identify subpopulations and fate of hepatic stellate cells (HSC) in murine liver. HSC are sinusoidal pericytes that act as myofibroblast precursors after liver injury. Single cell RNA sequencing approaches have recently helped to differentiate central and portal HSC. A specific Cre line to lineage trace portal HSC has not yet been described. We used three Cre lines (Lrat-Cre, PDGFRß-CreERT2 and SMMHC-CreERT2) known to label mesenchymal cells including HSC in combination with a tdTomato-expressing reporter. All three Cre lines labeled populations of HSC as well as smooth muscle cells (SMC). Using the SMMHC-CreERT2, we identified a subtype of HSC in the periportal area of the hepatic lobule (termed zone 1-HSC). We lineage traced tdTomato-expressing zone 1-HSC over 1 year, described fibrotic behavior in two fibrosis models and investigated their possible role during fibrosis. This HSC subtype resides in zone 1 under healthy conditions; however, zonation is disrupted in preclinical models of liver fibrosis (CCl4 and MASH). Zone 1-HSC do not transform into αSMA-expressing myofibroblasts. Rather, they participate in sinusoidal capillarization. We describe a novel subtype of HSC restricted to zone 1 under physiological conditions and its possible function after liver injury. In contrast to the accepted notion, this HSC subtype does not transform into αSMA-positive myofibroblasts; rather, zone 1-HSC adopt properties of capillary pericytes, thereby participating in sinusoidal capillarization.
Asunto(s)
Células Estrelladas Hepáticas , Cirrosis Hepática , Miofibroblastos , Animales , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Miofibroblastos/metabolismo , Miofibroblastos/patología , Ratones , Cirrosis Hepática/patología , Cirrosis Hepática/metabolismo , Hígado/patología , Hígado/metabolismo , Pericitos/metabolismo , Pericitos/patología , Linaje de la Célula , Masculino , Diferenciación Celular , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Tumours can obtain nutrients and oxygen required to progress and metastasize through the blood supply1. Inducing angiogenesis involves the sprouting of established vessel beds and their maturation into an organized network2,3. Here we generate a comprehensive atlas of tumour vasculature at single-cell resolution, encompassing approximately 200,000 cells from 372 donors representing 31 cancer types. Trajectory inference suggested that tumour angiogenesis was initiated from venous endothelial cells and extended towards arterial endothelial cells. As neovascularization elongates (through angiogenic stages SI, SII and SIII), APLN+ tip cells at the SI stage (APLN+ TipSI) advanced to TipSIII cells with increased Notch signalling. Meanwhile, stalk cells, following tip cells, transitioned from high chemokine expression to elevated TEK (also known as Tie2) expression. Moreover, APLN+ TipSI cells not only were associated with disease progression and poor prognosis but also hold promise for predicting response to anti-VEGF therapy. Lymphatic endothelial cells demonstrated two distinct differentiation lineages: one responsible for lymphangiogenesis and the other involved in antigen presentation. In pericytes, endoplasmic reticulum stress was associated with the proangiogenic BASP1+ matrix-producing pericytes. Furthermore, intercellular communication analysis showed that neovascular endothelial cells could shape an immunosuppressive microenvironment conducive to angiogenesis. This study depicts the complexity of tumour vasculature and has potential clinical significance for anti-angiogenic therapy.
Asunto(s)
Células Endoteliales , Neoplasias , Neovascularización Patológica , Análisis de la Célula Individual , Humanos , Presentación de Antígeno , Comunicación Celular , Diferenciación Celular , Linaje de la Célula , Progresión de la Enfermedad , Estrés del Retículo Endoplásmico , Células Endoteliales/citología , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Linfangiogénesis , Neoplasias/irrigación sanguínea , Neoplasias/clasificación , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neovascularización Patológica/patología , Pericitos/patología , Pericitos/citología , Pericitos/metabolismo , Pronóstico , Receptores Notch/metabolismo , Transducción de Señal , Microambiente Tumoral , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Pez CebraRESUMEN
BACKGROUND: Endothelial prolyl hydroxylase-2 (PHD2) is essential for pulmonary remodeling and hypertension. In the present study, we investigated the role of endothelial PHD2 in angiotensin II-mediated arterial stiffness, pericyte recruitment, and cardiac fibrosis. METHODS AND RESULTS: Chondroitin sulfate proteoglycan 4 tracing reporter chondroitin sulfate proteoglycan 4- red fluorescent protein (DsRed) transgenic mice were crossed with PHD2flox/flox (PHD2f/f) mice and endothelial-specific knockout of PHD2 (PHD2ECKO) mice. Transgenic PHD2f/f (TgPHD2f/f) mice and TgPHD2ECKO mice were infused with angiotensin II for 4 weeks. Arterial thickness, stiffness, and histological and immunofluorescence of pericytes and fibrosis were measured. Infusion of TgPHD2f/f mice with angiotensin II resulted in a time-dependent increase in pulse-wave velocity. Angiotensin II-induced pulse-wave velocity was further elevated in the TgPHD2ECKO mice. TgPHD2ECKO also reduced coronary flow reserve compared with TgPHD2f/f mice infused with angiotensin II. Mechanistically, knockout of endothelial PHD2 promoted aortic arginase activity and angiotensin II-induced aortic thickness together with increased transforming growth factor-ß1 and ICAM-1/VCAM-1 expression in coronary arteries. TgPHD2f/f mice infused with angiotensin II for 4 weeks exhibited a significant increase in cardiac fibrosis and hypertrophy, which was further developed in the TgPHD2ECKO mice. Chondroitin sulfate proteoglycan 4 pericyte was traced by DsRed+ staining and angiotensin II infusion displayed a significant increase of DsRed+ pericytes in the heart, as well as a deficiency of endothelial PHD2, which further promoted angiotensin II-induced pericyte increase. DsRed+ pericytes were costained with fibroblast-specific protein 1 and α-smooth muscle actin for measuring pericyte-myofibroblast cell transition. The knockout of endothelial PHD2 increased the amount of DsRed+/fibroblast-specific protein 1+ and DsRed+/α-smooth muscle actin+ cells induced by angiotensin II infusion. CONCLUSIONS: Knockout of endothelial PHD2 enhanced angiotensin II-induced cardiac fibrosis by mechanisms involving increasing arterial stiffness and pericyte-myofibroblast cell transitions.
Asunto(s)
Angiotensina II , Células Endoteliales , Fibrosis , Ratones Noqueados , Pericitos , Rigidez Vascular , Animales , Pericitos/patología , Pericitos/metabolismo , Angiotensina II/farmacología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Ratones , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/deficiencia , Miocardio/patología , Miocardio/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BLRESUMEN
Spinal cord injury (SCI) leads to fibrotic scar formation at the lesion site, yet the heterogeneity of fibrotic scar remains elusive. Here we show the heterogeneity in distribution, origin, and function of fibroblasts within fibrotic scars after SCI in mice and female monkeys. Utilizing lineage tracing and single-cell RNA sequencing (scRNA-seq), we found that perivascular fibroblasts (PFs), and meningeal fibroblasts (MFs), rather than pericytes/vascular smooth cells (vSMCs), primarily contribute to fibrotic scar in both transection and crush SCI. Crabp2 + /Emb+ fibroblasts (CE-F) derived from meninges primarily localize in the central region of fibrotic scars, demonstrating enhanced cholesterol synthesis and secretion of type I collagen and fibronectin. In contrast, perivascular/pial Lama1 + /Lama2+ fibroblasts (LA-F) are predominantly found at the periphery of the lesion, expressing laminin and type IV collagen and functionally involved in angiogenesis and lipid transport. These findings may provide a comprehensive understanding for remodeling heterogeneous fibrotic scars after SCI.
Asunto(s)
Cicatriz , Fibroblastos , Fibrosis , Laminina , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Cicatriz/patología , Cicatriz/metabolismo , Ratones , Femenino , Laminina/metabolismo , Meninges/patología , Meninges/metabolismo , Fibronectinas/metabolismo , Modelos Animales de Enfermedad , Colágeno Tipo I/metabolismo , Ratones Endogámicos C57BL , Pericitos/metabolismo , Pericitos/patología , Colágeno Tipo IV/metabolismo , Colesterol/metabolismoRESUMEN
Capillaries are the smallest blood vessels (<10 µm in diameter) in the body and their walls are lined by endothelial cells. These microvessels play a crucial role in nutrient and gas exchange between blood and tissues. Capillary endothelial cells also produce vasoactive molecules and initiate the electrical signals that underlie functional hyperemia and neurovascular coupling. Accordingly, capillary function and density are critical for all cell types to match blood flow to cellular activity. This begins with the process of angiogenesis, when new capillary blood vessels emerge from pre-existing vessels, and ends with rarefaction, the loss of these microvascular structures. This review explores the mechanisms behind these processes, emphasizing their roles in various microvascular diseases and their impact on surrounding cells in health and disease. We discuss recent work on the mechanisms controlling endothelial cell proliferation, migration, and tube formation that underlie angiogenesis under physiological and pathological conditions. The mechanisms underlying functional and anatomical rarefaction and the role of pericytes in this process are also discussed. Based on this work, a model is proposed in which the balance of angiogenic and rarefaction signaling pathways in a particular tissue match microvascular density to the metabolic demands of the surrounding cells. This negative feedback loop becomes disrupted during microvascular rarefaction: angiogenic mechanisms are blunted, reactive oxygen species accumulate, capillary function declines and eventually, capillaries disappear. This, we propose, forms the foundation of the reciprocal relationship between vascular density, blood flow, and metabolic needs and functionality of nearby cells.
Asunto(s)
Capilares , Células Endoteliales , Rarefacción Microvascular , Neovascularización Patológica , Neovascularización Fisiológica , Transducción de Señal , Humanos , Animales , Capilares/metabolismo , Capilares/fisiopatología , Capilares/patología , Neovascularización Patológica/fisiopatología , Neovascularización Patológica/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Rarefacción Microvascular/fisiopatología , Rarefacción Microvascular/metabolismo , Pericitos/metabolismo , Pericitos/patología , Proliferación Celular , Movimiento Celular , Densidad Microvascular , AngiogénesisRESUMEN
Pericytes (PCs) are versatile cells integral to the microcirculation wall, exhibiting specific stem cell traits. They are essential in modulating blood flow, ensuring vascular permeability, maintaining homeostasis, and aiding tissue repair process. Given their involvement in numerous disease-related pathological and physiological processes, the regulation of PCs has emerged as a focal point of research. Adenomyosis is characterized by the presence of active endometrial glands and stroma encased by an enlarged and proliferative myometrial layer, further accompanied by fibrosis and new blood vessel formation. This distinct pathological condition might be intricately linked with PCs. This article comprehensively reviews the markers associated with PCs, their contributions to angiogenesis, blood flow modulation, and fibrotic processes. Moreover, it provides a comprehensive overview of the current research on adenomyosis pathophysiology, emphasizing the potential correlation and future implications regarding PCs and the development of adenomyosis.
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Adenomiosis , Pericitos , Adenomiosis/patología , Adenomiosis/fisiopatología , Pericitos/patología , Humanos , Femenino , Neovascularización Patológica/patología , Animales , Fibrosis/patología , Endometrio/patología , Endometrio/irrigación sanguínea , Miometrio/patología , Biomarcadores/metabolismoRESUMEN
To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer's disease, we performed single nucleus RNA sequencing in 24 Alzheimer's disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer's disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer's disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer's disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer's disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3-astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer's disease.
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Enfermedad de Alzheimer , Astrocitos , Barrera Hematoencefálica , Pericitos , Proteína smad3 , Factor A de Crecimiento Endotelial Vascular , Pez Cebra , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Humanos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Proteína smad3/metabolismo , Proteína smad3/genética , Astrocitos/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Pericitos/metabolismo , Pericitos/patología , Masculino , Células Madre Pluripotentes Inducidas/metabolismo , Femenino , Anciano , Transcriptoma , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/irrigación sanguínea , Anciano de 80 o más Años , Modelos Animales de EnfermedadRESUMEN
Pericyte dysfunction, with excessive migration, hyperproliferation, and differentiation into smooth muscle-like cells contributes to vascular remodeling in Pulmonary Arterial Hypertension (PAH). Augmented expression and action of growth factors trigger these pathological changes. Endogenous factors opposing such alterations are barely known. Here, we examine whether and how the endothelial hormone C-type natriuretic peptide (CNP), signaling through the cyclic guanosine monophosphate (cGMP) -producing guanylyl cyclase B (GC-B) receptor, attenuates the pericyte dysfunction observed in PAH. The results demonstrate that CNP/GC-B/cGMP signaling is preserved in lung pericytes from patients with PAH and prevents their growth factor-induced proliferation, migration, and transdifferentiation. The anti-proliferative effect of CNP is mediated by cGMP-dependent protein kinase I and inhibition of the Phosphoinositide 3-kinase (PI3K)/AKT pathway, ultimately leading to the nuclear stabilization and activation of the Forkhead Box O 3 (FoxO3) transcription factor. Augmentation of the CNP/GC-B/cGMP/FoxO3 signaling pathway might be a target for novel therapeutics in the field of PAH.
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Proliferación Celular , GMP Cíclico , Proteína Forkhead Box O3 , Péptido Natriurético Tipo-C , Pericitos , Transducción de Señal , Humanos , Pericitos/metabolismo , Pericitos/patología , Péptido Natriurético Tipo-C/metabolismo , GMP Cíclico/metabolismo , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/genética , Masculino , Femenino , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/patología , Persona de Mediana Edad , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Adulto , Receptores del Factor Natriurético Atrial/metabolismo , Receptores del Factor Natriurético Atrial/genética , Células CultivadasRESUMEN
Intracranial atherosclerotic stenosis (ICAS) is a pathological condition characterized by progressive narrowing or complete blockage of intracranial blood vessels caused by plaque formation. This condition leads to reduced blood flow to the brain, resulting in cerebral ischemia and hypoxia. Ischemic stroke (IS) resulting from ICAS poses a significant global public health challenge, especially among East Asian populations. However, the underlying causes of the notable variations in prevalence among diverse populations, as well as the most effective strategies for preventing and treating the rupture and blockage of intracranial plaques, remain incompletely comprehended. Rupture of plaques, bleeding, and thrombosis serve as precipitating factors in the pathogenesis of luminal obstruction in intracranial arteries. Pericytes play a crucial role in the structure and function of blood vessels and face significant challenges in regulating the Vasa Vasorum (VV)and preventing intraplaque hemorrhage (IPH). This review aims to explore innovative therapeutic strategies that target the pathophysiological mechanisms of vulnerable plaques by modulating pericyte biological function. It also discusses the potential applications of pericytes in central nervous system (CNS) diseases and their prospects as a therapeutic intervention in the field of biological tissue engineering regeneration.
Asunto(s)
Pericitos , Pericitos/patología , Humanos , Animales , Arteriosclerosis Intracraneal/patología , Arteriosclerosis Intracraneal/fisiopatología , Vasa Vasorum/patología , Vasa Vasorum/fisiopatología , Arterias Cerebrales/patologíaRESUMEN
While inflammation is beneficial for insulin secretion during homeostasis, its transformation adversely affects ß cells and contributes to diabetes. However, the regulation of islet inflammation for maintaining glucose homeostasis remains largely unknown. Here, we identified pericytes as pivotal regulators of islet immune and ß cell function in health. Islets and pancreatic pericytes express various cytokines in healthy humans and mice. To interfere with the pericytic inflammatory response, we selectively inhibited the TLR/MyD88 pathway in these cells in transgenic mice. The loss of MyD88 impaired pericytic cytokine production. Furthermore, MyD88-deficient mice exhibited skewed islet inflammation with fewer cells, an impaired macrophage phenotype, and reduced IL-1ß production. This aberrant pericyte-orchestrated islet inflammation was associated with ß cell dedifferentiation and impaired glucose response. Additionally, we found that Cxcl1, a pericytic MyD88-dependent cytokine, promoted immune IL-1ß production. Treatment with either Cxcl1 or IL-1ß restored the mature ß cell phenotype and glucose response in transgenic mice, suggesting a potential mechanism through which pericytes and immune cells regulate glucose homeostasis. Our study revealed pericyte-orchestrated islet inflammation as a crucial element in glucose regulation, implicating this process as a potential therapeutic target for diabetes.
Asunto(s)
Inflamación , Interleucina-1beta , Factor 88 de Diferenciación Mieloide , Pericitos , Transducción de Señal , Animales , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Ratones , Pericitos/metabolismo , Pericitos/patología , Pericitos/inmunología , Humanos , Inflamación/patología , Inflamación/metabolismo , Inflamación/genética , Inflamación/inmunología , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Ratones Transgénicos , Receptores Toll-Like/metabolismo , Receptores Toll-Like/genética , Quimiocina CXCL1/metabolismo , Quimiocina CXCL1/genética , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Ratones Noqueados , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/inmunología , Masculino , Glucosa/metabolismoRESUMEN
Coronavirus disease 2019 (COVID-19) was initially considered a primarily respiratory disease but is now known to affect other organs including the heart and brain. A major route by which COVID-19 impacts different organs is via the vascular system. We studied the impact of apolipoprotein E (APOE) genotype and inflammation on vascular infectivity by pseudo-typed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses in mouse and human cultured endothelial cells and pericytes. Possessing the APOE4 allele or having existing systemic inflammation is known to enhance the severity of COVID-19. Using targeted replacement human APOE3 and APOE4 mice and inflammation induced by bacterial lipopolysaccharide (LPS), we investigated infection by SARS-CoV-2. Here, we show that infectivity was higher in murine cerebrovascular pericytes compared to endothelial cells and higher in cultures expressing APOE4. Furthermore, increasing the inflammatory state of the cells by prior incubation with LPS increased infectivity into human and mouse pericytes and human endothelial cells. Our findings provide insights into the mechanisms underlying severe COVID-19 infection, highlighting how risk factors such as APOE4 genotype and prior inflammation may exacerbate disease severity by augmenting the virus's ability to infect vascular cells.
Asunto(s)
COVID-19 , Células Endoteliales , Pericitos , SARS-CoV-2 , Pericitos/virología , Pericitos/metabolismo , Pericitos/patología , Humanos , Animales , SARS-CoV-2/fisiología , SARS-CoV-2/patogenicidad , COVID-19/virología , COVID-19/patología , Ratones , Células Endoteliales/virología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Factores de Riesgo , Lipopolisacáridos/farmacología , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Inflamación/virología , Inflamación/patologíaRESUMEN
Fibrotic scar tissue formation occurs in humans and mice. The fibrotic scar impairs tissue regeneration and functional recovery. However, the origin of scar-forming fibroblasts is unclear. Here, we show that stromal fibroblasts forming the fibrotic scar derive from two populations of perivascular cells after spinal cord injury (SCI) in adult mice of both sexes. We anatomically and transcriptionally identify the two cell populations as pericytes and perivascular fibroblasts. Fibroblasts and pericytes are enriched in the white and gray matter regions of the spinal cord, respectively. Both cell populations are recruited in response to SCI and inflammation. However, their contribution to fibrotic scar tissue depends on the location of the lesion. Upon injury, pericytes and perivascular fibroblasts become activated and transcriptionally converge on the generation of stromal myofibroblasts. Our results show that pericytes and perivascular fibroblasts contribute to the fibrotic scar in a region-dependent manner.