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Cells Nov 2021Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact... (Review)
Review
Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.
Topics: Animals; Blood Vessels; DNA, Mitochondrial; Endothelium, Vascular; Female; Humans; Oxidative Stress; Pre-Eclampsia; Pregnancy; Toll-Like Receptor 9
PubMed: 34831277
DOI: 10.3390/cells10113055 -
Science (New York, N.Y.) Mar 2022Cerebrovascular diseases are a leading cause of death and neurologic disability. Further understanding of disease mechanisms and therapeutic strategies requires a deeper...
Cerebrovascular diseases are a leading cause of death and neurologic disability. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of cerebrovascular cells in humans. We profiled transcriptomes of 181,388 cells to define a cell atlas of the adult human cerebrovasculature, including endothelial cell molecular signatures with arteriovenous segmentation and expanded perivascular cell diversity. By leveraging this reference, we investigated cellular and molecular perturbations in brain arteriovenous malformations, which are a leading cause of stroke in young people, and identified pathologic endothelial transformations with abnormal vascular patterning and the ontology of vascularly derived inflammation. We illustrate the interplay between vascular and immune cells that contributes to brain hemorrhage and catalog opportunities for targeting angiogenic and inflammatory programs in vascular malformations.
Topics: Adult; Blood Vessels; Brain; Cells, Cultured; Cerebral Cortex; Cerebral Hemorrhage; Cerebrovascular Circulation; Endothelial Cells; Fibroblasts; Humans; Inflammation; Intracranial Arteriovenous Malformations; Monocytes; Muscle, Smooth, Vascular; Pericytes; RNA-Seq; Single-Cell Analysis; Transcriptome
PubMed: 35084939
DOI: 10.1126/science.abi7377 -
Cells Oct 2020Perivascular inflammation is a prominent pathologic feature in most animal models of pulmonary hypertension (PH) as well as in pulmonary arterial hypertension (PAH)... (Review)
Review
Perivascular inflammation is a prominent pathologic feature in most animal models of pulmonary hypertension (PH) as well as in pulmonary arterial hypertension (PAH) patients. Accumulating evidence suggests a functional role of perivascular inflammation in the initiation and/or progression of PAH and pulmonary vascular remodeling. High levels of cytokines, chemokines, and inflammatory mediators can be detected in PAH patients and correlate with clinical outcome. Similarly, multiple immune cells, including neutrophils, macrophages, dendritic cells, mast cells, T lymphocytes, and B lymphocytes characteristically accumulate around pulmonary vessels in PAH. Concomitantly, vascular and parenchymal cells including endothelial cells, smooth muscle cells, and fibroblasts change their phenotype, resulting in altered sensitivity to inflammatory triggers and their enhanced capacity to stage inflammatory responses themselves, as well as the active secretion of cytokines and chemokines. The growing recognition of the interaction between inflammatory cells, vascular cells, and inflammatory mediators may provide important clues for the development of novel, safe, and effective immunotargeted therapies in PAH.
Topics: Animals; Biomarkers; Blood Vessels; Cytokines; Disease Susceptibility; Humans; Inflammation; Inflammation Mediators; Pulmonary Arterial Hypertension; Vascular Remodeling
PubMed: 33105588
DOI: 10.3390/cells9112338 -
Cells Aug 2021Vascularization of tissues, organoids and organ-on-chip models has been attempted using endothelial cells. However, the cultured endothelial cells lack the capacity to...
Vascularization of tissues, organoids and organ-on-chip models has been attempted using endothelial cells. However, the cultured endothelial cells lack the capacity to interact with other somatic cell types, which is distinct from developing vascular cells in vivo. Recently, it was demonstrated that blood vessel organoids (BVOs) recreate the structure and functions of developing human blood vessels. However, the tissue-specific adaptability of BVOs had not been assessed in somatic tissues. Herein, we investigated whether BVOs infiltrate human cerebral organoids and form a blood-brain barrier. As a result, vascular cells arising from BVOs penetrated the cerebral organoids and developed a vessel-like architecture composed of CD31 endothelial tubes coated with SMA or PDGFR mural cells. Molecular markers of the blood-brain barrier were detected in the vascularized cerebral organoids. We revealed that BVOs can form neural-specific blood-vessel networks that can be maintained for over 50 days.
Topics: Blood Vessels; Blood-Brain Barrier; Brain; Coculture Techniques; Endothelial Cells; Endothelium; Humans; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Organoids; Platelet Endothelial Cell Adhesion Molecule-1; Receptors, Platelet-Derived Growth Factor
PubMed: 34440805
DOI: 10.3390/cells10082036 -
Angiogenesis May 2021There are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen,... (Review)
Review
There are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.
Topics: Animals; Blood Vessels; Endothelial Cells; Humans; Lymphatic Vessels; Vascular Malformations
PubMed: 33844116
DOI: 10.1007/s10456-021-09785-7 -
Arteriosclerosis, Thrombosis, and... Jul 2019Aortic aneurysm is a vascular disease whereby the ECM (extracellular matrix) of a blood vessel degenerates, leading to dilation and eventually vessel wall rupture.... (Review)
Review
Aortic aneurysm is a vascular disease whereby the ECM (extracellular matrix) of a blood vessel degenerates, leading to dilation and eventually vessel wall rupture. Recently, it was shown that calcification of the vessel wall is involved in both the initiation and progression of aneurysms. Changes in aortic wall structure that lead to aneurysm formation and vascular calcification are actively mediated by vascular smooth muscle cells. Vascular smooth muscle cells in a healthy vessel wall are termed contractile as they maintain vascular tone and remain quiescent. However, in pathological conditions they can dedifferentiate into a synthetic phenotype, whereby they secrete extracellular vesicles, proliferate, and migrate to repair injury. This process is called phenotypic switching and is often the first step in vascular pathology. Additionally, healthy vascular smooth muscle cells synthesize VKDPs (vitamin K-dependent proteins), which are involved in inhibition of vascular calcification. The metabolism of these proteins is known to be disrupted in vascular pathologies. In this review, we summarize the current literature on vascular smooth muscle cell phenotypic switching and vascular calcification in relation to aneurysm. Moreover, we address the role of vitamin K and VKDPs that are involved in vascular calcification and aneurysm. Visual Overview- An online visual overview is available for this article.
Topics: Aortic Aneurysm; Elastin; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxidative Stress; Phenotype; Transforming Growth Factor beta; Vascular Calcification; Vitamin K; Vitamin K Epoxide Reductases
PubMed: 31144989
DOI: 10.1161/ATVBAHA.119.312787 -
Circulation Research Jun 2021Vascular and lymphatic malformations represent a challenge for clinicians. The identification of inherited and somatic mutations in important signaling pathways,... (Review)
Review
Vascular and lymphatic malformations represent a challenge for clinicians. The identification of inherited and somatic mutations in important signaling pathways, including the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin), RAS (rat sarcoma)/RAF (rapidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinases), HGF (hepatocyte growth factor)/c-Met (hepatocyte growth factor receptor), and VEGF (vascular endothelial growth factor) A/VEGFR (vascular endothelial growth factor receptor) 2 cascades has led to the evaluation of tailored strategies with preexisting cancer drugs that interfere with these signaling pathways. The era of theranostics has started for the treatment of vascular anomalies. Registration: URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2015-001703-32.
Topics: Angiogenesis Inhibitors; Animals; Blood Vessels; Genetic Predisposition to Disease; Humans; Molecular Targeted Therapy; Mutation; Neovascularization, Physiologic; Phenotype; Protein Kinase Inhibitors; Signal Transduction; Vascular Malformations
PubMed: 34166070
DOI: 10.1161/CIRCRESAHA.121.318145 -
The Journal of Clinical Investigation Feb 2021Abnormal angiogenesis and regression of the diseased retinal vasculature are key processes associated with ischemic retinopathies, but the underlying mechanisms that...
Abnormal angiogenesis and regression of the diseased retinal vasculature are key processes associated with ischemic retinopathies, but the underlying mechanisms that regulate vascular remodeling remain poorly understood. Here, we confirmed the specific expression of semaphorin 3G (Sema3G) in retinal endothelial cells (ECs), which was required for vascular remodeling and the amelioration of ischemic retinopathy. We found that Sema3G was elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and in the neovascularization regression phase of oxygen-induced retinopathy (OIR). Endothelial-specific Sema3G knockout mice exhibited decreased vessel density and excessive matrix deposition in the retinal vasculature. Moreover, loss of Sema3G aggravated pathological angiogenesis in mice with OIR. Mechanistically, we demonstrated that HIF-2α directly regulated Sema3G transcription in ECs under hypoxia. Sema3G coordinated the functional interaction between β-catenin and VE-cadherin by increasing β-catenin stability in the endothelium through the neuropilin-2 (Nrp2)/PlexinD1 receptor. Furthermore, Sema3G supplementation enhanced healthy vascular network formation and promoted diseased vasculature regression during blood vessel remodeling. Overall, we deciphered the endothelium-derived Sema3G-dependent events involved in modulating physiological vascular remodeling and regression of pathological blood vessels for reparative vascular regeneration. Our findings shed light on the protective effect of Sema3G in ischemic retinopathies.
Topics: Animals; Endothelium, Vascular; Female; Humans; Ischemia; Male; Mice; Mice, Transgenic; Retinal Diseases; Retinal Vessels; Semaphorins; Vascular Remodeling; beta Catenin
PubMed: 33586674
DOI: 10.1172/JCI135296 -
Nature Feb 2021In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining...
In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining myelopoiesis-the differentiation of myeloid progenitors into a large variety of innate immune cells-in situ in the bone marrow. Such strategies are required to understand differentiation and lineage-commitment decisions, and to define how spatial organizing cues inform tissue function. Here we develop approaches for imaging myelopoiesis in mice, and generate atlases showing the differentiation of granulocytes, monocytes and dendritic cells. The generation of granulocytes and dendritic cells-monocytes localizes to different blood-vessel structures known as sinusoids, and displays lineage-specific spatial and clonal architectures. Acute systemic infection with Listeria monocytogenes induces lineage-specific progenitor clusters to undergo increased self-renewal of progenitors, but the different lineages remain spatially separated. Monocyte-dendritic cell progenitors (MDPs) map with nonclassical monocytes and conventional dendritic cells; these localize to a subset of blood vessels expressing a major regulator of myelopoiesis, colony-stimulating factor 1 (CSF1, also known as M-CSF). Specific deletion of Csf1 in endothelium disrupts the architecture around MDPs and their localization to sinusoids. Subsequently, there are fewer MDPs and their ability to differentiate is reduced, leading to a loss of nonclassical monocytes and dendritic cells during both homeostasis and infection. These data indicate that local cues produced by distinct blood vessels are responsible for the spatial organization of definitive blood cell differentiation.
Topics: Animals; Atlases as Topic; Blood Vessels; Cell Lineage; Cell Self Renewal; Cell Tracking; Dendritic Cells; Endothelium, Vascular; Female; Granulocytes; Listeria monocytogenes; Listeriosis; Macrophage Colony-Stimulating Factor; Male; Mice; Monocytes; Myeloid Cells; Myelopoiesis; Staining and Labeling
PubMed: 33568812
DOI: 10.1038/s41586-021-03201-2 -
Nature Communications Oct 2021Defective pericyte-endothelial cell interaction in tumors leads to a chaotic, poorly organized and dysfunctional vasculature. However, the underlying mechanism behind...
Defective pericyte-endothelial cell interaction in tumors leads to a chaotic, poorly organized and dysfunctional vasculature. However, the underlying mechanism behind this is poorly studied. Herein, we develop a method that combines magnetic beads and flow cytometry cell sorting to isolate pericytes from tumors and normal adjacent tissues from patients with non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC). Pericytes from tumors show defective blood vessel supporting functions when comparing to those obtained from normal tissues. Mechanistically, combined proteomics and metabolic flux analysis reveals elevated hexokinase 2(HK2)-driven glycolysis in tumor pericytes, which up-regulates their ROCK2-MLC2 mediated contractility leading to impaired blood vessel supporting function. Clinically, high percentage of HK2 positive pericytes in blood vessels correlates with poor patient overall survival in NSCLC and HCC. Administration of a HK2 inhibitor induces pericyte-MLC2 driven tumor vasculature remodeling leading to enhanced drug delivery and efficacy against tumor growth. Overall, these data suggest that glycolysis in tumor pericytes regulates their blood vessel supporting role.
Topics: A549 Cells; Animals; Blood Vessels; Cardiac Myosins; Cell Line, Tumor; Cell Proliferation; Endothelial Cells; Gene Expression Regulation, Neoplastic; Glycolysis; Hexokinase; Humans; Mice; Mice, Inbred C57BL; Myosin Light Chains; Neoplasms; Neoplasms, Vascular Tissue; Pericytes; Tumor Microenvironment; Up-Regulation; rho-Associated Kinases
PubMed: 34650057
DOI: 10.1038/s41467-021-26259-y