The neurobiology of long COVID

Neuron, Journal Year: 2022, Volume and Issue: 110(21), P. 3484 - 3496

Published: Oct. 7, 2022

Persistent neurological and neuropsychiatric symptoms affect a substantial fraction of people after COVID-19 represent major component the post-acute syndrome, also known as long COVID. Here, we review what is understood about pathobiology impact on CNS discuss possible neurobiological underpinnings cognitive affecting survivors. We propose chief mechanisms that may contribute to this emerging health crisis.

Language: Английский

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Pathological angiogenesis: mechanisms and therapeutic strategies

Angiogenesis, Journal Year: 2023, Volume and Issue: 26(3), P. 313 - 347

Published: April 15, 2023

In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, coalescent well vessel co-option, vasculogenic mimicry lymphangiogenesis, underlie vasculature. many pathological conditions, cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but often done so without normal feedback that regulate ordinary spatial temporal patterns formation. Thus, angiogenesis presents challenges yet opportunities design vascular-directed therapies. Here, we provide overview recent insights into development highlight novel therapeutic strategies promote or inhibit to stabilize, reverse, even halt disease progression. our review, will also explore several additional aspects (the switch, hypoxia, angiocrine signals, endothelial plasticity, normalization, cell anergy) operate in parallel canonical speculate how these may be targeted with anti-angiogenic

Language: Английский

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Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics

Cells, Journal Year: 2023, Volume and Issue: 12(5), P. 816 - 816

Published: March 6, 2023

The development of long-term symptoms coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed "long COVID" or post-acute sequela COVID-19 (PASC), can implicate persistent neurological complications in up to one third patients and present as fatigue, "brain fog", headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, peripheral neuropathy. Pathogenic mechanisms these long COVID remain largely unclear; however, several hypotheses both nervous system systemic pathogenic such SARS-CoV2 viral persistence neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, endotheliopathy. Outside the CNS, SARS-CoV-2 invade support stem cells olfactory epithelium leading alterations function. infection may induce abnormalities innate adaptive immunity including monocyte expansion, T-cell exhaustion, prolonged cytokine release, which cause neuroinflammatory responses microglia activation, white matter abnormalities, microvascular changes. Additionally, clot formation occlude capillaries endotheliopathy, due protease activity complement contribute hypoxic neuronal injury blood-brain barrier dysfunction, respectively. Current therapeutics target pathological by employing antivirals, decreasing inflammation, promoting regeneration. Thus, from laboratory evidence clinical trials literature, we sought synthesize pathophysiological pathways underlying potential therapeutics.

Language: Английский

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Pericytes in the disease spotlight

Trends in Cell Biology, Journal Year: 2023, Volume and Issue: 34(1), P. 58 - 71

Published: July 18, 2023

Molecular and functional pericyte studies at single-cell resolution are providing new insights into long-standing questions about heterogeneity.Pericytes not identified by a single marker but instead gene expression signatures that show substantial inter-organ differences.Pericytes orchestrate precede endothelial cell responses during angiogenesis.Pericyte degeneration dysfunction, triggered the onset of some diseases, contribute to progression those diseases in both vascular non-vascular contexts.The number with dysfunction continues expand, thereby anticipating promising future for pericyte-focused therapy. Pericytes classically defined as mural cells (see Glossary) envelop endothelium small caliber blood vessels, so-called capillaries. embedded within same basement membrane (ECs) interact closely them [1.Armulik A. et al.Pericytes: developmental, physiological, pathological perspectives, problems, promises.Dev. Cell. 2011; 21: 193-215Abstract Full Text PDF PubMed Scopus (1790) Google Scholar,2.Holm al.Microvascular organotypic heterogeneity plasticity.Trends Cell Biol. 2018; 28: 302-316Abstract (63) Scholar]. By contrast, smooth muscle (vSMCs), other type, cover large arteries veins, physically separated from an intimal layer extracellular matrix (ECM). Of note, lymphatic capillaries lack pericytes under physiological conditions, although collecting vessels contain vSMCs [3.Petrova T.V. Koh G.Y. Biological functions vessels.Science. 2020; 369eaax4063Crossref (144) A fundamental function is regulate stabilization vessels. It therefore surprising loss were linked several including cancer cerebrovascular more than decade ago [4.Martin J.D. al.Normalizing tumor vessels: progress, opportunities, challenges.Annu. Rev. Physiol. 2019; 81: 505-534Crossref (242) Scholar,5.Lendahl U. al.Emerging links between neurodegenerative diseases-a special role pericytes.EMBO Rep. 20e48070Crossref (71) However, therapies have been poorly explored. Instead, most on vascular-directed therapeutic strategies ECs – central components build Emerging data are, however, changing perception mere supporting recruited final stage vessel formation essential elements early phases angiogenesis anticipate EC behavior. In addition, recent research revealing novel roles beyond their implications vasculature. Collectively, we believe these open exciting avenues approaches call broader understanding disease progression. We provide here global overview significant advances regarding our different pathobiological scenarios discuss field's current paradigms controversies. First, address associated responses. Second, evidence disease, cell-autonomous For comprehensive details biology, ontology, specific signaling pathways, refer reader importance, emerging concepts biology described following sections only studied one tissue. To avoid confusion generalizability properties, frame each considering relevant organ study. exhibit inter- intra-tissue molecular differences exert tissue-specific [2.Holm Their molecular, morphological, inextricably diverse developmental origins, modes recruitment, anatomical localization. example, nervous system (CNS) microvasculature firmly continuously invested around support barrier whereas liver pericytes, commonly referred hepatic stellate (HSCs), reside perisinusoidal space, loosely discontinuously ECs, hold unique vitamin storage capacity meet demands, distribution density variable among organs beds, CNS showing greatest pericyte-to-EC abundance. From standpoint there no can exclusively identify (Box 1), albeit emergence techniques shedding light markers functions. first atlas types brain adult mice RNA sequencing (scRNA-seq) revealed follow gradient transitional phenotypes. This occurs interface precapillary arterioles, capillaries, postcapillary venules, does continuum along arteriovenous axis (Figure 1 Box 1) [6.Vanlandewijck M. al.A zonation vasculature.Nature. 554: 475-480Crossref (876) Whether this phenotypes specifically restricted vasculature or also present beds remains be determined. Indeed, many 2 illustrates three top-ranked enriched per organ), which transporters contractile machinery [7.Muhl L. al.Single-cell analysis uncovers fibroblast criteria identification discrimination.Nat. Commun. 11: 3953Crossref (187) Another intriguing observation cross-organ Scholar,8.Muhl transcriptomic inventory murine cells.Dev. 2022; 57: 2426-2443Abstract Currently, inter-tissue behavior two main completely understood. may because greater cell-intrinsic plasticity adapt portfolio fulfill universal across tissues. contrast differences, transcription factors appears relatively conserved organs, suggesting subtypes epigenetic mechanisms Accordingly, DNA hypermethylation was recently found control alpha actin (αSMA) renal after ischemia [9.Chou Y.H. al.Methylation acute injury promotes chronic kidney disease.J. Clin. Invest. 130: 4845-4857Crossref (18) indicates methods such assay transposase-accessible chromatin (ATAC-seq) will instrumental further understand phenotypes.Box 1Unraveling identity pericytesThe challenging task. Despite ongoing efforts, consensus unambiguous identification. date all distinguish types, scRNA-seq now opportunities discern tissue specificity Scholar,71.Teuwen L.A. al.Tumor co-option probed analysis.Cell 2021; 35109253Abstract (35) Scholar,93.Baek S.H. al.Single reveals identities.Front Cardiovasc. Med. 9876591Crossref (9) The use transgenic reporter mouse models has label, trace, locate populations vivo. combination multiple lines often necessary properly discriminate perivascular Scholar, 7.Muhl 8.Muhl Mural highly plastic cells; phenotypic do Figure 1A,B text) transcriptional point view, distinct continuums cells: (i) capillary venous (SMCs), where gradually transition SMC phenotype, (ii) arterial SMCs pattern towards arteriole SMCs. resemblance venular Scholar], well classic led hypothesis transcriptionally morphologically similar Human recapitulate pattern, human evenly distributed over veins [50.Yang A.C. mediators Alzheimer's risk.Nature. 603: 885-892Crossref (117) Scholar,94.Garcia F.J. dissection 893-899Crossref (53) Unlike separation brain, discerned functionality marked solute transport (ECM) organization Unfortunately, ability predict presence limited, select few retain adequate specificity. zebrafish better alternative study genes [95.Shih al.Integrated identifies signature zebrafish.Development. 148dev200189Crossref (4) RGS5, NDUFA4L2, KNCJ8, HIGD1B, ABCC9, NOTCH3, PDGFRB currently species markers, detailed characterization when studying text).Figure 2Organotypic markers.Show full captionThis figure summarizes heart, lung, kidney, colon (upper row) (lower row). Pericyte chosen based stringent evaluation abundance, specificity, homogeneity utilizing information provided Scholar,50.Yang Scholar,82.Muhl al.The SARS-CoV-2 receptor ACE2 expressed COVID-19 research.Stem 17: 1089-1104Abstract (0) Scholar,84.Dobie R. transcriptomics mesenchyme fibrosis.Cell 29: 1832-1847Abstract (164) Scholar,85.Kuppe C. al.Decoding myofibroblast origins fibrosis.Nature. 589: 281-286Crossref (225) Scholar,95.Shih Scholar,100.Winkler E.A. normal malformed vasculature.Science. 375: eabi7377Crossref (5) 101.Travaglini K.J. lung sequencing.Nature. 587: 619-625Crossref (470) 102.Kinchen J. al.Structural remodeling colonic inflammatory bowel disease.Cell. 175: 372-386Abstract (313) Validation selected situ used second selection.View Large Image ViewerDownload Hi-res image Download (PPT) text). selection. Many documented [10.Potente al.Basic aspects angiogenesis.Cell. 146: 873-887Abstract (1978) historical view proposes mainly late stages Scholar,10.Potente taking advantage retina paradigmatic experimental model angiogenesis, concept challenged [11.Park D.Y. al.Plastic blood-retinal barrier.Nat. 2017; 8: 15296Crossref (175) 12.Figueiredo A.M. al.Phosphoinositide 3-kinase-regulated maturation governs remodeling.Circulation. 142: 688-704Crossref (25) 13.Orlich M.M. al.Mural SRF controls migration, patterning flow.Circ. Res. 131: 308-327Crossref 14.Dieguez-Hurtado al.Loss factor RBPJ induces disease-promoting properties pericytes.Nat. 10: 2817Crossref 15.Teichert al.Pericyte-expressed Tie2 maturation.Nat. 16106Crossref (174) 16.Eilken H.M. al.Pericytes VEGF-induced sprouting through VEGFR1.Nat. 1574Crossref (134) showed that, yet achieved maturity seen formed permissive cell-cycle progression, morphological adaptation, migration [12.Figueiredo Scholar,13.Orlich setting, growth precedes expansion it still unclear why. One possibility expanding rapidly, ensure production sufficient signals, coherent inhibition activation blocks proliferation Scholar] nuclear translocation FOXO1 master regulator quiescence [17.Kobialka P. Graupera Revisiting PI3-kinase signalling angiogenesis.Vasc. 1: H125-H134Crossref examined absent, become angiogenic able proliferate [18.Mae M.A. blood–brain response loss.Circ. 128: e46-e62Crossref require expand. Nonetheless, fair acknowledge shown reduced coverage leads increased [19.Dave J.M. al.Pericyte ALK5/TIMP3 contributes morphogenesis developing brain.Dev. 47: 388-389Abstract (8) Although discrepancies highlight pericyte–EC interactions complex, they explained animal genetic interfere pericytes. Importantly, behaviors mostly tissues belonging CNS. Hence, given high abundance CNS, possible substantially outnumber them. interesting immature remain close contact entirety Scholar,20.Crouch E.E. al.Ensembles promote prenatal brain.Cell. 185: 3753-3769Abstract (11) suggests communication relies paracrine juxtracrine signaling, explain why Pu

Language: Английский

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SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 15, 2024

Abstract Background Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element human tissues reservoirs is the main product of mRNA COVID-19 vaccines. We investigated whether alone triggers pro-inflammatory pro-coagulant responses primary cultures two cell types deeply affected by SARS-CoV-2, such monocytes cells. Methods In umbilical vein cells (HUVEC) monocytes, components NF-κB NLRP3 inflammasome system, well coagulation regulators, were assessed qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence. Results activated NF-κB, promoted cytokines release, triggered priming activation system resulting mature IL-1β formation both types. This was paralleled enhanced production factors von Willebrand factor (vWF), VIII tissue factor, that mediated, at least part, IL-1β. Additionally, failed to enhance ADAMTS-13 levels counteract activity vWF multimers. Monocytes HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches gene silencing showed TLR4 receptors mediated effects but not HUVEC. Conclusion behaves a stimulus Interfering with signaling pathways evoked may help preventing immune vascular complications driven viral element.

Language: Английский

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A single-cell transcriptomic inventory of murine smooth muscle cells

Developmental Cell, Journal Year: 2022, Volume and Issue: 57(20), P. 2426 - 2443.e6

Published: Oct. 1, 2022

Smooth muscle cells (SMCs) execute important physiological functions in numerous vital organ systems, including the vascular, gastrointestinal, respiratory, and urogenital tracts. SMC differ morphologically functionally at these different anatomical locations, but molecular underpinnings of differences remain poorly understood. Here, using deep single-cell RNA sequencing combined with situ gene protein expression analysis four murine organs-heart, aorta, lung, colon-we identify a basis for high-level among visceral, airway SMC, as well more subtle between, example, elastic muscular arteries zonation artery along direction blood flow. Arterial exhibit extensive organotypic heterogeneity, whereas venous are similar across organs. We further specific subtype within pulmonary vasculature. This comparative cross-organ resource offers insight into subtypes their functions.

Language: Английский

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Risk of Thrombosis during and after a SARS-CoV-2 Infection: Pathogenesis, Diagnostic Approach, and Management

Hematology Reports, Journal Year: 2023, Volume and Issue: 15(2), P. 225 - 243

Published: April 3, 2023

Coronavirus disease 2019 (COVID-19) increases the risk of thromboembolic events, especially in patients with severe infections requiring intensive care and cardiorespiratory support. COVID-19 complications have a higher death, if they survive, these are expected to negatively affect patients’ quality life. Moreover, recent data reported that thromboembolism remains high months after infection. Therefore, understanding pathogenesis thrombosis setting may facilitate early prevention treatment COVID-19-associated reduce concomitant morbidity, mortality, disability. This review will first discuss clinical characteristics infections, particularly regard underlying pathophysiology. Then, at molecular cellular levels be comprehensively reviewed. Next, manifestations venous arterial as well potential benefits several laboratory markers further discussed. Lastly, preventive therapeutic management during also explained.

Language: Английский

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Pericyte Loss in Diseases

Cells, Journal Year: 2023, Volume and Issue: 12(15), P. 1931 - 1931

Published: July 26, 2023

Pericytes are specialized cells located in close proximity to endothelial within the microvasculature. They play a crucial role regulating blood flow, stabilizing vessel walls, and maintaining integrity of blood–brain barrier. The loss pericytes has been associated with development progression various diseases, such as diabetes, Alzheimer’s disease, sepsis, stroke, traumatic brain injury. This review examines detection pericyte different explores methods employed assess coverage, elucidates potential mechanisms contributing these pathological conditions. Additionally, current therapeutic strategies targeting discussed, along future interventions aimed at preserving function promoting disease mitigation.

Language: Английский

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Single-cell atlas of human pancreatic islet and acinar endothelial cells in health and diabetes

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 6, 2025

Characterization of the vascular heterogeneity within pancreas has previously been lacking. Here, we develop strategies to enrich islet-specific endothelial cells (ISECs) and acinar-specific (ASECs) from three human pancreases corroborate these findings with published pancreatic datasets. Single-cell RNA sequencing reveals unique molecular signatures ISECs, including structural genes COL13A1, ESM1, PLVAP, UNC5B, LAMA4, angiocrine KDR, THBS1, BMPs CXCR4, metabolic ACE, PASK F2RL3. ASECs display distinct GPIHBP1, CCL14, CD74, AQP1, KLF4, KLF2, which may manage inflammatory needs exocrine pancreas. Ligand-receptor analysis suggests ISECs interact LUM+ fibroblasts RGS5+ pericytes smooth muscle via VEGF-A:VEGFR2, CXCL12:CXCR4, LIF:LIFR pathways. Comparative expression immunohistochemistry indicate disruption endothelial-expressed THBD, VWA1, VEGF-A cross-talk among other cell types in diabetes. Thus, our data provide a single-cell atlas pancreas, enabling deeper understanding pathophysiology health disease.

Language: Английский

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SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction

Brain, Journal Year: 2022, Volume and Issue: 146(2), P. 727 - 738

Published: July 22, 2022

Abstract The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an sequence similar to human evoked a small pericyte-mediated capillary constriction via AT1 receptors, but large when the receptor binding domain (RBD, original Wuhan variant) was present. A mutated non-binding RBD did not potentiate constriction. RBD-potentiated occurred in cortical slices, hamster by pseudotyped virions expressing spike protein. This reflects RBD-induced decrease conversion of angiotensin-(1-7) mediated removal cell surface membrane mimicked blocking ACE2. clinically used drug losartan inhibited Thus, blockers could be protective COVID-19 preventing flow reductions perhaps kidney.

Language: Английский

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