RESUMO
B cells are traditionally known for their ability to produce antibodies in the context of adaptive immune responses. However, over the last decade B cells have been increasingly recognized as modulators of both adaptive and innate immune responses, as well as players in an important role in the pathogenesis of a variety of human diseases. Here, after briefly summarizing our current understanding of B cell biology, we present a systematic review of the literature from both animal models and human studies that highlight the important role that B lymphocytes play in cardiac and vascular disease. While many aspects of B cell biology in the vasculature and, to an even greater extent, in the heart remain unclear, B cells are emerging as key regulators of cardiovascular adaptation to injury.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Suscetibilidade a Doenças , Imunidade Adaptativa , Animais , Doenças Cardiovasculares/diagnóstico , Citocinas/metabolismo , Humanos , Imunidade Inata , Mediadores da Inflamação/metabolismoRESUMO
The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet. Developmental ablation of Fam19a4/Nts-RGCs led to disoriented growth of penetrating vessels near the ganglion cell layer (GCL), leading to a disorganized 3D vascular lattice. We identified enriched PIEZO2 expression in Fam19a4/Nts-RGCs. Piezo2 loss from all retinal neurons or Fam19a4/Nts-RGCs abolished the direct neurovascular contacts and phenocopied the Fam19a4/Nts-RGC ablation deficits. The defective vascular structure led to reduced capillary perfusion and sensitized the retina to ischemic insults. Furthermore, we uncovered a Piezo2-dependent perivascular granule cell subset for cerebellar vascular patterning, indicating neuronal Piezo2-dependent 3D vascular patterning in the brain.
Assuntos
Cerebelo , Neurônios , Retina , Animais , Feminino , Masculino , Camundongos , Cerebelo/metabolismo , Cerebelo/irrigação sanguínea , Cerebelo/citologia , Canais Iônicos/metabolismo , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Retina/citologia , Retina/metabolismo , Células Ganglionares da Retina/metabolismo , Vasos Retinianos/metabolismoRESUMO
Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+ release and mitogen-activated protein kinase (MAPK) pathway activation. The high specificity of the designed agonists reveals distinct roles for two FGFR splice variants in driving arterial endothelium and perivascular cell fates during early vascular development. Our designed modular assemblies should be broadly useful for unraveling the complexities of signaling in key developmental transitions and for developing future therapeutic applications.
Assuntos
Diferenciação Celular , Fatores de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos , Transdução de Sinais , Animais , Humanos , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Camundongos , Ligantes , Cálcio/metabolismo , Sistema de Sinalização das MAP QuinasesRESUMO
A functional network of blood vessels is essential for organ growth and homeostasis, yet how the vasculature matures and maintains homeostasis remains elusive in live mice. By longitudinally tracking the same neonatal endothelial cells (ECs) over days to weeks, we found that capillary plexus expansion is driven by vessel regression to optimize network perfusion. Neonatal ECs rearrange positions to evenly distribute throughout the developing plexus and become positionally stable in adulthood. Upon local ablation, adult ECs survive through a plasmalemmal self-repair response, while neonatal ECs are predisposed to die. Furthermore, adult ECs reactivate migration to assist vessel repair. Global ablation reveals coordinated maintenance of the adult vascular architecture that allows for eventual network recovery. Lastly, neonatal remodeling and adult maintenance of the skin vascular plexus are orchestrated by temporally restricted, neonatal VEGFR2 signaling. Our work sheds light on fundamental mechanisms that underlie both vascular maturation and adult homeostasis in vivo.
Assuntos
Células Endoteliais , Neovascularização Fisiológica , Animais , Camundongos , Células Endoteliais/fisiologia , Neovascularização Fisiológica/fisiologia , Pele , Membrana CelularRESUMO
The evolution and development of the head have long captivated researchers due to the crucial role of the head as the gateway for sensory stimuli and the intricate structural complexity of the head. Although significant progress has been made in understanding head development in various vertebrate species, our knowledge of early human head ontogeny remains limited. Here, we used advanced whole-mount immunostaining and 3D imaging techniques to generate a comprehensive 3D cellular atlas of human head embryogenesis. We present detailed developmental series of diverse head tissues and cell types, including muscles, vasculature, cartilage, peripheral nerves, and exocrine glands. These datasets, accessible through a dedicated web interface, provide insights into human embryogenesis. We offer perspectives on the branching morphogenesis of human exocrine glands and unknown features of the development of neurovascular and skeletomuscular structures. These insights into human embryology have important implications for understanding craniofacial defects and neurological disorders and advancing diagnostic and therapeutic strategies.
Assuntos
Embrião de Mamíferos , Cabeça , Humanos , Morfogênese , Cabeça/crescimento & desenvolvimentoRESUMO
The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFα, and NF-κB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19.
Assuntos
COVID-19/complicações , COVID-19/imunologia , SARS-CoV-2/genética , Trombose/complicações , Doenças Vasculares/complicações , Idoso de 80 Anos ou mais , Animais , Lavagem Broncoalveolar , Proteína C-Reativa/análise , COVID-19/sangue , COVID-19/patologia , Ativação do Complemento , Citocinas/sangue , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Inflamação/virologia , Pulmão/patologia , Macaca mulatta , Macrófagos/imunologia , Masculino , Ativação Plaquetária , Trombose/sangue , Trombose/patologia , Transcriptoma , Doenças Vasculares/sangue , Doenças Vasculares/patologiaRESUMO
The cerebral vasculature is a dense network of arteries, capillaries, and veins. Quantifying variations of the vascular organization across individuals, brain regions, or disease models is challenging. We used immunolabeling and tissue clearing to image the vascular network of adult mouse brains and developed a pipeline to segment terabyte-sized multichannel images from light sheet microscopy, enabling the construction, analysis, and visualization of vascular graphs composed of over 100 million vessel segments. We generated datasets from over 20 mouse brains, with labeled arteries, veins, and capillaries according to their anatomical regions. We characterized the organization of the vascular network across brain regions, highlighting local adaptations and functional correlates. We propose a classification of cortical regions based on the vascular topology. Finally, we analysed brain-wide rearrangements of the vasculature in animal models of congenital deafness and ischemic stroke, revealing that vascular plasticity and remodeling adopt diverging rules in different models.
Assuntos
Adaptação Fisiológica , Encéfalo/irrigação sanguínea , Capilares/anatomia & histologia , Artérias Cerebrais/anatomia & histologia , Veias Cerebrais/anatomia & histologia , Remodelação Vascular , Animais , Capilares/patologia , Artérias Cerebrais/patologia , Veias Cerebrais/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Privação Sensorial , Estresse Psicológico/etiologia , Estresse Psicológico/patologia , Acidente Vascular Cerebral/patologiaRESUMO
KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescence-associated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8+ T cells into otherwise immunologically "cold" tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.
Assuntos
Envelhecimento/fisiologia , Carcinoma Ductal Pancreático/patologia , Remodelação Vascular/fisiologia , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/microbiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Genes ras/genética , Humanos , Imunoterapia/métodos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Neoplasias Pancreáticas/patologia , Proteína do Retinoblastoma/imunologia , Transdução de Sinais/genética , Microambiente Tumoral , Remodelação Vascular/genéticaRESUMO
Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology.
Assuntos
Mecanotransdução Celular , Interferência de RNA , Receptores Acoplados a Proteínas G/fisiologia , Animais , Materiais Biocompatíveis , Cálcio/metabolismo , Linhagem Celular Tumoral , Células Endoteliais/fisiologia , Endotélio Vascular/citologia , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração de Íons de Hidrogênio , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores Acoplados a Proteínas G/genética , Resistência ao Cisalhamento , Estresse Mecânico , Resistência VascularRESUMO
The 9p21.3 cardiovascular disease locus is the most influential common genetic risk factor for coronary artery disease (CAD), accounting for â¼10%-15% of disease in non-African populations. The â¼60 kb risk haplotype is human-specific and lacks coding genes, hindering efforts to decipher its function. Here, we produce induced pluripotent stem cells (iPSCs) from risk and non-risk individuals, delete each haplotype using genome editing, and generate vascular smooth muscle cells (VSMCs). Risk VSMCs exhibit globally altered transcriptional networks that intersect with previously identified CAD risk genes and pathways, concomitant with aberrant adhesion, contraction, and proliferation. Unexpectedly, deleting the risk haplotype rescues VSMC stability, while expressing the 9p21.3-associated long non-coding RNA ANRIL induces risk phenotypes in non-risk VSMCs. This study shows that the risk haplotype selectively predisposes VSMCs to adopt a cell state associated with CAD phenotypes, defines new VSMC-based networks of CAD risk genes, and establishes haplotype-edited iPSCs as powerful tools for functionally annotating the human genome.
Assuntos
Cromossomos Humanos Par 9 , Doença da Artéria Coronariana , Edição de Genes , Haplótipos , Células-Tronco Pluripotentes Induzidas , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 9/genética , Cromossomos Humanos Par 9/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Feminino , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transcrição GênicaRESUMO
Maladaptive, non-resolving inflammation contributes to chronic inflammatory diseases such as atherosclerosis. Because macrophages remove necrotic cells, defective macrophage programs can promote chronic inflammation with persistent tissue injury. Here, we investigated the mechanisms sustaining vascular macrophages. Intravital imaging revealed a spatiotemporal macrophage niche across vascular beds alongside mural cells (MCs)-pericytes and smooth muscle cells. Single-cell transcriptomics, co-culture, and genetic deletion experiments revealed MC-derived expression of the chemokines CCL2 and MIF, which actively preserved macrophage survival and their homeostatic functions. In atherosclerosis, this positioned macrophages in viable plaque areas, away from the necrotic core, and maintained a homeostatic macrophage phenotype. Disruption of this MC-macrophage unit via MC-specific deletion of these chemokines triggered detrimental macrophage relocalizing, exacerbated plaque necrosis, inflammation, and atheroprogression. In line, CCL2 inhibition at advanced stages of atherosclerosis showed detrimental effects. This work presents a MC-driven safeguard toward maintaining the homeostatic vascular macrophage niche.
Assuntos
Aterosclerose , Placa Aterosclerótica , Humanos , Macrófagos/metabolismo , Aterosclerose/metabolismo , Placa Aterosclerótica/metabolismo , Quimiocinas/metabolismo , Inflamação/metabolismo , Necrose/metabolismoRESUMO
This review aims to survey the current state of mechanotransduction in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), including their sensing of mechanical stimuli and transduction of mechanical signals that result in the acute functional modulation and longer-term transcriptomic and epigenetic regulation of blood vessels. The mechanosensors discussed include ion channels, plasma membrane-associated structures and receptors, and junction proteins. The mechanosignaling pathways presented include the cytoskeleton, integrins, extracellular matrix, and intracellular signaling molecules. These are followed by discussions on mechanical regulation of transcriptome and epigenetics, relevance of mechanotransduction to health and disease, and interactions between VSMCs and ECs. Throughout this review, we offer suggestions for specific topics that require further understanding. In the closing section on conclusions and perspectives, we summarize what is known and point out the need to treat the vasculature as a system, including not only VSMCs and ECs but also the extracellular matrix and other types of cells such as resident macrophages and pericytes, so that we can fully understand the physiology and pathophysiology of the blood vessel as a whole, thus enhancing the comprehension, diagnosis, treatment, and prevention of vascular diseases.
Assuntos
Células Endoteliais , Mecanotransdução Celular , Humanos , Mecanotransdução Celular/fisiologia , Células Endoteliais/metabolismo , Epigênese Genética , Transdução de Sinais/fisiologia , Miócitos de Músculo Liso , Estresse MecânicoRESUMO
In addition to their conventional role as a versatile transport system, blood vessels provide signals controlling organ development, regeneration, and stem cell behavior. In the skeletal system, certain capillaries support perivascular osteoprogenitor cells and thereby control bone formation. Blood vessels are also a critical component of niche microenvironments for hematopoietic stem cells. Here we discuss key pathways and factors controlling endothelial cell behavior in bone, the role of vessels in osteogenesis, and the nature of vascular stem cell niches in bone marrow.
Assuntos
Vasos Sanguíneos/metabolismo , Hematopoese , Osteogênese , Transdução de Sinais , Animais , Medula Óssea/irrigação sanguínea , Células Endoteliais/metabolismo , HumanosRESUMO
Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system. From the onset of blood flow, the embryonic vasculature is continuously exposed to a variety of hemodynamic forces. These biomechanical stimuli are key determinants of vascular cell specification and remodeling and the establishment of vascular homeostasis. In recent years, major advances have been made in our understanding of mechano-activated signaling networks that control both spatiotemporal and structural aspects of vascular development. It has become apparent that a major site for mechanotransduction is situated at the interface of blood and the vessel wall and that this process is controlled by the vascular endothelium. In this review, we discuss the hemodynamic control of endothelial cell fates, focusing on arterial-venous specification, lymphatic development, and the endothelial-to-hematopoietic transition, and present some recent insights into the mechano-activated pathways driving these cell fate decisions in the developing embryo.
Assuntos
Linhagem da Célula , Desenvolvimento Embrionário , Células Endoteliais/citologia , Hemodinâmica , Animais , Humanos , Mecanotransdução Celular , ReologiaRESUMO
Cytosolic DNA acts as a universal danger-associated molecular pattern (DAMP) signal; however, the mechanisms of self-DNA release into the cytosol and its role in inflammatory tissue injury are not well understood. We found that the internalized bacterial endotoxin lipopolysaccharide (LPS) activated the pore-forming protein Gasdermin D, which formed mitochondrial pores and induced mitochondrial DNA (mtDNA) release into the cytosol of endothelial cells. mtDNA was recognized by the DNA sensor cGAS and generated the second messenger cGAMP, which suppressed endothelial cell proliferation by downregulating YAP1 signaling. This indicated that the surviving endothelial cells in the penumbrium of the inflammatory injury were compromised in their regenerative capacity. In an experimental model of inflammatory lung injury, deletion of cGas in mice restored endothelial regeneration. The results suggest that targeting the endothelial Gasdermin D activated cGAS-YAP signaling pathway could serve as a potential strategy for restoring endothelial function after inflammatory injury.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ciclo Celular/genética , Proliferação de Células/genética , DNA Mitocondrial/genética , Células Endoteliais/metabolismo , Inflamação/genética , Nucleotidiltransferases/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Citosol/metabolismo , DNA Mitocondrial/metabolismo , Células Endoteliais/citologia , Células HEK293 , Humanos , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nucleotídeos Cíclicos/metabolismo , Nucleotidiltransferases/metabolismo , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/metabolismo , Transdução de Sinais , Proteínas de Sinalização YAPRESUMO
Lymphocyte homeostasis and immune surveillance require that T and B cells continuously recirculate between secondary lymphoid organs. Here, we used intravital microscopy to define lymphocyte trafficking routes within the spleen, an environment of open blood circulation and shear forces unlike other lymphoid organs. Upon release from arterioles into the red pulp sinuses, T cells latched onto perivascular stromal cells in a manner that was independent of the chemokine receptor CCR7 but sensitive to Gi protein-coupled receptor inhibitors. This latching sheltered T cells from blood flow and enabled unidirectional migration to the bridging channels and then to T zones, entry into which required CCR7. Inflammatory responses modified the chemotactic cues along the perivascular homing paths, leading to rapid block of entry. Our findings reveal a role for vascular structures in lymphocyte recirculation through the spleen, indicating the existence of separate entry and exit routes and that of a checkpoint located at the gate to the T zone.
Assuntos
Movimento Celular/imunologia , Receptores CCR7/imunologia , Baço/imunologia , Linfócitos T/imunologia , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Humanos , Vigilância Imunológica/imunologia , Microscopia Intravital , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Linfócitos/citologia , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores CCR7/genética , Receptores CCR7/metabolismo , Transdução de Sinais/imunologia , Baço/citologia , Baço/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismoRESUMO
Epithelioid hemangioendothelioma (EHE) is a poorly understood and devastating vascular cancer. Sequencing of EHE has revealed a unique gene fusion between the Hippo pathway nuclear effector TAZ (WWTR1) and the brain-enriched transcription factor CAMTA1 in â¼90% of cases. However, it remains unclear whether the TAZ-CAMTA1 gene fusion is a driver of EHE, and potential targeted therapies are unknown. Here, we show that TAZ-CAMTA1 expression in endothelial cells is sufficient to drive the formation of vascular tumors with the distinctive features of EHE, and inhibition of TAZ-CAMTA1 results in the regression of these vascular tumors. We further show that activated TAZ resembles TAZ-CAMTA1 in driving the formation of EHE-like vascular tumors, suggesting that constitutive activation of TAZ underlies the pathological features of EHE. We show that TAZ-CAMTA1 initiates an angiogenic and regenerative-like transcriptional program in endothelial cells, and disruption of the TAZ-CAMTA1-TEAD interaction or ectopic expression of a dominant negative TEAD in vivo inhibits TAZ-CAMTA1-mediated transformation. Our study provides the first genetic model of a TAZ fusion oncoprotein driving its associated human cancer, pinpointing TAZ-CAMTA1 as the key driver and a valid therapeutic target of EHE.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Carcinogênese/genética , Células Endoteliais/patologia , Regulação Neoplásica da Expressão Gênica , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transativadores/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular Tumoral , Fusão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Transativadores/genética , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.
Assuntos
Neoplasias , Pericitos , Humanos , Pericitos/patologia , Pericitos/fisiologia , Guanilil Ciclase Solúvel , Células Endoteliais/fisiologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neoplasias/genética , Neoplasias/patologia , Guanilato Ciclase , Microambiente TumoralRESUMO
Endothelial cell responses to fluid shear stress from blood flow are crucial for vascular development, function, and disease. A complex of PECAM-1, VE-cadherin, VEGF receptors (VEGFRs), and Plexin D1 located at cell-cell junctions mediates many of these events. However, available evidence suggests that another mechanosensor upstream of PECAM-1 initiates signaling. Hypothesizing that GPCR and Gα proteins may serve this role, we performed siRNA screening of Gα subunits and found that Gαi2 and Gαq/11 are required for activation of the junctional complex. We then developed a new activation assay, which showed that these G proteins are activated by flow. We next mapped the Gα residues required for activation and developed an affinity purification method that used this information to identify latrophilin-2 (Lphn2/ADGRL2) as the upstream GPCR. Latrophilin-2 is required for all PECAM-1 downstream events tested. In both mice and zebrafish, latrophilin-2 is required for flow-dependent angiogenesis and artery remodeling. Furthermore, endothelial-specific knockout demonstrates that latrophilin plays a role in flow-dependent artery remodeling. Human genetic data reveal a correlation between the latrophilin-2-encoding Adgrl2 gene and cardiovascular disease. Together, these results define a pathway that connects latrophilin-dependent G protein activation to subsequent endothelial signaling, vascular physiology, and disease.
Assuntos
Junções Intercelulares , Mecanotransdução Celular , Receptores Acoplados a Proteínas G , Receptores de Peptídeos , Animais , Humanos , Camundongos , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Junções Intercelulares/metabolismo , Junções Intercelulares/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/metabolismo , Receptores de Peptídeos/genética , Estresse Mecânico , Peixe-Zebra/metabolismo , Peixe-Zebra/genéticaRESUMO
The elastic properties of conductance arteries are one of the most important hemodynamic functions in the body, and data continue to emerge regarding the importance of their dysfunction in vascular aging and a range of cardiovascular diseases. Here, we provide new insight into the integrative physiology of arterial stiffening and its clinical consequence. We also comprehensively review progress made on pathways/molecules that appear today as important basic determinants of arterial stiffness, particularly those mediating the vascular smooth muscle cell (VSMC) contractility, plasticity and stiffness. We focus on membrane and nuclear mechanotransduction, clearance function of the vascular wall, phenotypic switching of VSMCs, immunoinflammatory stimuli and epigenetic mechanisms. Finally, we discuss the most important advances of the latest clinical studies that revisit the classical therapeutic concepts of arterial stiffness and lead to a patient-by-patient strategy according to cardiovascular risk exposure and underlying disease.