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Circulation Research Feb 2021Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described...
RATIONALE
Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive.
OBJECTIVE
To map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level and to correlate them with regional heterogeneities in BBB function and vascular phenotype.
METHODS AND RESULTS
We reveal transcriptional, morphological, and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses, and immunofluorescent detection of protein expression in pericyte-deficient adult mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB.
CONCLUSIONS
By elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence, and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 (angiopoietin 2) is paradoxical given its wider role as TIE2 (TEK receptor tyrosine kinase) receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.
Topics: Animals; Blood-Brain Barrier; Cell Proliferation; Cells, Cultured; Endothelial Cells; Lymphokines; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Pericytes; Platelet-Derived Growth Factor; Single-Cell Analysis; Transcriptome
PubMed: 33375813
DOI: 10.1161/CIRCRESAHA.120.317473 -
Theranostics 2022Microvascular complication is a major cause of morbidity and mortality among the patients with diabetes. Pericyte dysfunction is the predominant pathological...
Microvascular complication is a major cause of morbidity and mortality among the patients with diabetes. Pericyte dysfunction is the predominant pathological manifestation of microvascular complication. -methyladenosine (mA) serves as the most prevalent modification in eukaryotic mRNAs. However, the role of mA RNA modification in pericyte dysfunction is still unclear. Quantitative polymerase chain reactions and western blots were conducted to detect the change of mA RNA modification in pericytes and mouse retinas following diabetic stress. MTT assay, transwell migration assay, caspase 3/7 activity assay, calcein-AM/propidium iodide (PI) staining, and TUNEL staining were conducted to determine the role of METTL3 in pericyte biology . Retinal trypsin digestion, vascular permeability assay, and IB4-NG2 double immunofluorescent staining were conducted to determine the role of METTL3 in retinal pericyte dysfunction and vascular complication. RNA sequencing, RNA pull-down assays and immunoblots were conducted to clarify the mechanism of METTL3-mediated pericyte dysfunction and vascular complication. The levels of mA RNA methylation were significantly up-regulated in pericytes and mouse retinas following diabetic stress, which were caused by increased expression of METTL3. METTL3 regulated the viability, proliferation, and differentiation of pericytes . Specific depletion of METTL3 in pericytes suppressed diabetes-induced pericyte dysfunction and vascular complication . METTL3 overexpression impaired pericyte function by repressing PKC-η, FAT4, and PDGFRA expression, which was mediated by YTHDF2-dependent mRNA decay. METTL3-mediated mA methylation epigenetically regulates diabetes-induced pericyte dysfunction. METTL3-YTHDF2-PKC-η/FAT4/PDGFRA signaling axis could be therapeutically targeted for treating microvascular complications.
Topics: Animals; Cell Line; Diabetes Mellitus; Diabetic Retinopathy; Humans; Methyltransferases; Mice; Mice, Inbred C57BL; Mice, Knockout; Pericytes
PubMed: 34987645
DOI: 10.7150/thno.63441 -
Nature Sep 2020Signalling between cells of the neurovascular unit, or neurovascular coupling, is essential to match local blood flow with neuronal activity. Pericytes interact with...
Signalling between cells of the neurovascular unit, or neurovascular coupling, is essential to match local blood flow with neuronal activity. Pericytes interact with endothelial cells and extend processes that wrap capillaries, covering up to 90% of their surface area. Pericytes are candidates to regulate microcirculatory blood flow because they are strategically positioned along capillaries, contain contractile proteins and respond rapidly to neuronal stimulation, but whether they synchronize microvascular dynamics and neurovascular coupling within a capillary network was unknown. Here we identify nanotube-like processes that connect two bona fide pericytes on separate capillary systems, forming a functional network in the mouse retina, which we named interpericyte tunnelling nanotubes (IP-TNTs). We provide evidence that these (i) have an open-ended proximal side and a closed-ended terminal (end-foot) that connects with distal pericyte processes via gap junctions, (ii) carry organelles including mitochondria, which can travel along these processes, and (iii) serve as a conduit for intercellular Ca waves, thus mediating communication between pericytes. Using two-photon microscope live imaging, we demonstrate that retinal pericytes rely on IP-TNTs to control local neurovascular coupling and coordinate light-evoked responses between adjacent capillaries. IP-TNT damage following ablation or ischaemia disrupts intercellular Ca waves, impairing blood flow regulation and neurovascular coupling. Notably, pharmacological blockade of Ca influx preserves IP-TNTs, rescues light-evoked capillary responses and restores blood flow after reperfusion. Our study thus defines IP-TNTs and characterizes their critical role in regulating neurovascular coupling in the living retina under both physiological and pathological conditions.
Topics: Animals; Brain Ischemia; Calcium; Calcium Signaling; Capillaries; Cell Communication; Female; Gap Junctions; Hemodynamics; Male; Mice; Mitochondria; Nanotubes; Neurovascular Coupling; Pericytes; Retina
PubMed: 32788726
DOI: 10.1038/s41586-020-2589-x -
Nature Neuroscience May 2021The majority of the brain's vasculature is composed of intricate capillary networks lined by capillary pericytes. However, it remains unclear whether capillary pericytes...
The majority of the brain's vasculature is composed of intricate capillary networks lined by capillary pericytes. However, it remains unclear whether capillary pericytes influence blood flow. Using two-photon microscopy to observe and manipulate brain capillary pericytes in vivo, we find that their optogenetic stimulation decreases lumen diameter and blood flow, but with slower kinetics than similar stimulation of mural cells on upstream pial and precapillary arterioles. This slow vasoconstriction was inhibited by the clinically used vasodilator fasudil, a Rho-kinase inhibitor that blocks contractile machinery. Capillary pericytes were also slower to constrict back to baseline following hypercapnia-induced dilation, and slower to dilate towards baseline following optogenetically induced vasoconstriction. Optical ablation of single capillary pericytes led to sustained local dilation and a doubling of blood cell flux selectively in capillaries lacking pericyte contact. These data indicate that capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain.
Topics: Animals; Brain; Capillaries; Cerebrovascular Circulation; Hemodynamics; Mice; Pericytes
PubMed: 33603231
DOI: 10.1038/s41593-020-00793-2 -
Nature Reviews. Cardiology Feb 2024Millions of cardiomyocytes die immediately after myocardial infarction, regardless of whether the culprit coronary artery undergoes prompt revascularization. Residual... (Review)
Review
Millions of cardiomyocytes die immediately after myocardial infarction, regardless of whether the culprit coronary artery undergoes prompt revascularization. Residual ischaemia in the peri-infarct border zone causes further cardiomyocyte damage, resulting in a progressive decline in contractile function. To date, no treatment has succeeded in increasing the vascularization of the infarcted heart. In the past decade, new approaches that can target the heart's highly plastic perivascular niche have been proposed. The perivascular environment is populated by mesenchymal progenitor cells, fibroblasts, myofibroblasts and pericytes, which can together mount a healing response to the ischaemic damage. In the infarcted heart, pericytes have crucial roles in angiogenesis, scar formation and stabilization, and control of the inflammatory response. Persistent ischaemia and accrual of age-related risk factors can lead to pericyte depletion and dysfunction. In this Review, we describe the phenotypic changes that characterize the response of cardiac pericytes to ischaemia and the potential of pericyte-based therapy for restoring the perivascular niche after myocardial infarction. Pericyte-related therapies that can salvage the area at risk of an ischaemic injury include exogenously administered pericytes, pericyte-derived exosomes, pericyte-engineered biomaterials, and pharmacological approaches that can stimulate the differentiation of constitutively resident pericytes towards an arteriogenic phenotype. Promising preclinical results from in vitro and in vivo studies indicate that pericytes have crucial roles in the treatment of coronary artery disease and the prevention of post-ischaemic heart failure.
Topics: Humans; Pericytes; Myocardial Infarction; Myocytes, Cardiac; Ischemia; Coronary Vessels
PubMed: 37542118
DOI: 10.1038/s41569-023-00913-y -
Advances in Experimental Medicine and... 2018The role of pericytes seems to extend beyond their known function in angiogenesis, fibrosis and wound healing, blood-brain barrier maintenance, and blood flow... (Review)
Review
The role of pericytes seems to extend beyond their known function in angiogenesis, fibrosis and wound healing, blood-brain barrier maintenance, and blood flow regulation. More and more data are currently accumulating indicating that pericytes, uniquely positioned at the interface between blood and parenchyma, secrete a large plethora of different molecules in response to microenvironmental changes. Their secretome is tissue-specific and stimulus-specific and includes pro- and anti-inflammatory factors, growth factors, and extracellular matrix as well as microvesicles suggesting the important role of pericytes in the regulation of immune response and immune evasion of tumors. However, the angiogenic and trophic secretome of pericytes indicates that their secretome plays a role in physiological homeostasis but possibly also in disease progression or could be exploited for regenerative processes in the future. This book chapter summarizes the current data on the secretory properties of pericytes from different tissues in response to certain pathological stimuli such as inflammatory stimuli, hypoxia, high glucose, and others and thereby aims to provide insights into the possible role of pericytes in these conditions.
Topics: Cell-Derived Microparticles; Extracellular Matrix; Homeostasis; Humans; Intercellular Signaling Peptides and Proteins; Metabolome; Pericytes
PubMed: 30523595
DOI: 10.1007/978-3-030-02601-1_11 -
Advances in Experimental Medicine and... 2019Pericytes are pluripotent cells found in the vascular wall of both capillaries and large blood vessels. Pericytes are highly heterogeneous cells in terms of phenotype,...
Pericytes are pluripotent cells found in the vascular wall of both capillaries and large blood vessels. Pericytes are highly heterogeneous cells in terms of phenotype, tissue distribution, origin and functions, and they play an important role in the regulation of vascular morphogenesis and function. Pericytes were shown to be involved in tissue development and homeostasis, as well as in pathological processes, including atherosclerosis. Both microvascular and macrovascular pericytes form the cellular network of the arterial wall and are actively involved in lipid accumulation, growth, and neovascularization of the atherosclerotic plaque, local inflammation and thrombosis. According to current understanding, pericytes originate from the multipotent stem cells capable of mesenchymal differentiation to oligopotent lineages, such as osteoclasts, chondrocytes, and adipocytes, and also serve as mesenchymal local progenitors in tissues. Pericyte multilineage potential is fundamental for vascular pathology, including atherosclerotic lesion formation. Pericytes express various surface proteins that can be used for their identification in aid of diagnosis and therapeutic strategies for atherosclerosis and other vascular pathologies.
Topics: Atherosclerosis; Cell Differentiation; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic; Pericytes
PubMed: 31147883
DOI: 10.1007/978-3-030-16908-4_13 -
Advances in Experimental Medicine and... 2019Mural cells known as pericytes envelop the endothelial layer of microvessels throughout the body and have been described to have tissue-specific functions. Cardiac... (Review)
Review
Mural cells known as pericytes envelop the endothelial layer of microvessels throughout the body and have been described to have tissue-specific functions. Cardiac pericytes are abundantly found in the heart, but they are relatively understudied. Currently, their importance is emerging in cardiovascular homeostasis and dysfunction due to their pleiotropism. They are known to play key roles in vascular tone and vascular integrity as well as angiogenesis. However, their dysfunctional presence and/or absence is critical in the mechanisms that lead to cardiac pathologies such as myocardial infarction, fibrosis, and thrombosis. Moreover, they are targeted as a therapeutic potential due to their mesenchymal properties that could allow them to repair and regenerate a damaged heart. They are also sought after as a cell-based therapy based on their healing potential in preclinical studies of animal models of myocardial infarction. Therefore, recognizing the importance of cardiac pericytes and understanding their biology will lead to new therapeutic concepts.
Topics: Animals; Heart; Humans; Microvessels; Myocardium; Neovascularization, Physiologic; Pericytes; Regeneration
PubMed: 30937870
DOI: 10.1007/978-3-030-11093-2_11 -
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