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Nature Jan 2019The increasing prevalence of diabetes has resulted in a global epidemic. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and amputation of...
The increasing prevalence of diabetes has resulted in a global epidemic. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and amputation of lower limbs. These are often caused by changes in blood vessels, such as the expansion of the basement membrane and a loss of vascular cells. Diabetes also impairs the functions of endothelial cells and disturbs the communication between endothelial cells and pericytes. How dysfunction of endothelial cells and/or pericytes leads to diabetic vasculopathy remains largely unknown. Here we report the development of self-organizing three-dimensional human blood vessel organoids from pluripotent stem cells. These human blood vessel organoids contain endothelial cells and pericytes that self-assemble into capillary networks that are enveloped by a basement membrane. Human blood vessel organoids transplanted into mice form a stable, perfused vascular tree, including arteries, arterioles and venules. Exposure of blood vessel organoids to hyperglycaemia and inflammatory cytokines in vitro induces thickening of the vascular basement membrane. Human blood vessels, exposed in vivo to a diabetic milieu in mice, also mimic the microvascular changes found in patients with diabetes. DLL4 and NOTCH3 were identified as key drivers of diabetic vasculopathy in human blood vessels. Therefore, organoids derived from human stem cells faithfully recapitulate the structure and function of human blood vessels and are amenable systems for modelling and identifying the regulators of diabetic vasculopathy, a disease that affects hundreds of millions of patients worldwide.
Topics: Adaptor Proteins, Signal Transducing; Amyloid Precursor Protein Secretases; Animals; Arteries; Arterioles; Basement Membrane; Blood Vessels; Calcium-Binding Proteins; Diabetic Angiopathies; Endothelial Cells; Humans; Hyperglycemia; In Vitro Techniques; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Mice; Models, Biological; Organoids; Pericytes; Pluripotent Stem Cells; Receptor, Notch3; Signal Transduction; Venules
PubMed: 30651639
DOI: 10.1038/s41586-018-0858-8 -
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 -
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 -
Cell Metabolism Nov 2016Hypoxic tumor-associated macrophages (TAMs) acquire angiogenic and immunosuppressive properties. Yet it remains unknown if metabolic changes influence these functions....
Hypoxic tumor-associated macrophages (TAMs) acquire angiogenic and immunosuppressive properties. Yet it remains unknown if metabolic changes influence these functions. Here, we argue that hypoxic TAMs strongly upregulate the expression of REDD1, a negative regulator of mTOR. REDD1-mediated mTOR inhibition hinders glycolysis in TAMs and curtails their excessive angiogenic response, with consequent formation of abnormal blood vessels. Accordingly, REDD1 deficiency in TAMs leads to the formation of smoothly aligned, pericyte-covered, functional vessels, which prevents vessel leakiness, hypoxia, and metastases. Mechanistically, highly glycolytic REDD1-deficient TAMs outcompete endothelial cells for glucose usage that thwarts vascular hyperactivation and promotes the formation of quiescent vascular junctions. Tuning down glycolysis in REDD1 knockout TAMs re-establishes abnormal angiogenesis and metastases. On this basis, we prove that the anti-tumor effect of mTOR inhibitors is partly countered by the deleterious outcome of these drugs on TAMs. Our data provide a functional link between TAM metabolism and tumor angiogenesis.
Topics: Animals; Blood Vessels; Cell Hypoxia; Disease Models, Animal; Endothelial Cells; Gene Deletion; Glucose; Glycolysis; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Morphogenesis; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factors; Up-Regulation
PubMed: 27773694
DOI: 10.1016/j.cmet.2016.09.008 -
Current Opinion in Hematology May 2019Recent advances in genetic evaluation improved the identification of several variants in the NOTCH3 gene causing Cerebral Autosomal Dominant Arteriopathy with... (Review)
Review
PURPOSE OF REVIEW
Recent advances in genetic evaluation improved the identification of several variants in the NOTCH3 gene causing Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Despite improved diagnosis, the disease mechanism remains an elusive target and an increasing number of scientific/clinical groups are investigating CADASIL to better understand it. The purpose of this review is to summarize the current knowledge in CADASIL.
RECENT FINDINGS
CADASIL is a genotypically and phenotypically diverse condition involving multiple molecular systems affecting small blood vessels. Cerebral white matter changes observed by MRI are a key CADASIL characteristic in young adult patients often before severe symptoms and trigger NOTCH3 genetic testing. NOTCH3 mutation locations are highly variable, correlate to disease severity and consistently affect the cysteine balance within extracellular Notch3. Granular osmiophilic material deposits around blood vessels are also a unique CADASIL feature and appear to have a role in sequestering proteins that are essential for blood vessel homeostasis. As potential biomarkers and therapeutic targets are being actively investigated, neurofilament light chain can be detected in patient serum and may be a promising circulating biomarker.
SUMMARY
CADASIL is a complex, devastating disease with unknown mechanism and no treatment options. As we increase our understanding of CADASIL, translational research bridging basic science and clinical findings needs to drive biomarker and therapeutic target discovery.
Topics: Animals; Blood Vessels; CADASIL; Genetic Testing; Humans; Receptor, Notch3; Translational Research, Biomedical
PubMed: 30855338
DOI: 10.1097/MOH.0000000000000497 -
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 -
Scientific Data Aug 2018Vascular diseases are major causes of death, yet our understanding of the cellular constituents of blood vessels, including how differences in their gene expression...
Vascular diseases are major causes of death, yet our understanding of the cellular constituents of blood vessels, including how differences in their gene expression profiles create diversity in vascular structure and function, is limited. In this paper, we describe a single-cell RNA sequencing (scRNA-seq) dataset that defines vascular and vessel-associated cell types and subtypes in mouse brain and lung. The dataset contains 3,436 single cell transcriptomes from mouse brain, which formed 15 distinct clusters corresponding to cell (sub)types, and another 1,504 single cell transcriptomes from mouse lung, which formed 17 cell clusters. In order to allow user-friendly access to our data, we constructed a searchable database (http://betsholtzlab.org/VascularSingleCells/database.html). Our dataset constitutes a comprehensive molecular atlas of vascular and vessel-associated cell types in the mouse brain and lung, and as such provides a strong foundation for future studies of vascular development and diseases.
Topics: Animals; Blood Vessels; Brain; Databases, Factual; Endothelial Cells; Lung; Mice; Myocytes, Smooth Muscle; Pericytes; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome
PubMed: 30129931
DOI: 10.1038/sdata.2018.160 -
Comprehensive Physiology Mar 2016A review is presented of the physical principles governing the distribution of blood flow and blood pressure in the vascular system. The main factors involved are the... (Review)
Review
A review is presented of the physical principles governing the distribution of blood flow and blood pressure in the vascular system. The main factors involved are the pulsatile driving pressure generated by the heart, the flow characteristics of blood, and the geometric structure and mechanical properties of the vessels. The relationship between driving pressure and flow in a given vessel can be understood by considering the viscous and inertial forces acting on the blood. Depending on the vessel diameter and other physical parameters, a wide variety of flow phenomena can occur. In large arteries, the propagation of the pressure pulse depends on the elastic properties of the artery walls. In the microcirculation, the fact that blood is a suspension of cells strongly influences its flow properties and leads to a nonuniform distribution of hematocrit among microvessels. The forces acting on vessel walls include shear stress resulting from blood flow and circumferential stress resulting from blood pressure. Biological responses to these forces are important in the control of blood flow and the structural remodeling of vessels, and also play a role in major disease processes including hypertension and atherosclerosis. Consideration of hemodynamics is essential for a comprehensive understanding of the functioning of the circulatory system.
Topics: Animals; Blood Vessels; Hemodynamics; Humans; Models, Cardiovascular
PubMed: 27065172
DOI: 10.1002/cphy.c150038 -
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