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HORSE diseases, ENDOTHELIAL cells, HORSE health, NEOVASCULARIZATION, CARDIOVASCULAR system, MUSCULOSKELETAL system, MALE reproductive organs, and GONADS

The cardiovascular system is the first functional organ in the embryo, and its blood vessels form a widespread conductive network within the organism. Blood vessels develop de novo, by the differentiation of endothelial progenitor cells (vasculogenesis) or by angiogenesis, which is the formation of new blood vessels from existing ones. This review presents an overview of the current knowledge on physiological and pathological angiogenesis in the horse including studies on equine endothelial cells. Principal study fields in equine angiogenesis research were identified: equine endothelial progenitor cells; equine endothelial cells and angiogenesis (heterogeneity, markers and assessment); endothelial regulatory molecules in equine angiogenesis; angiogenesis research in equine reproduction (ovary, uterus, placenta and conceptus, testis); angiogenesis research in pathological conditions (tumours, ocular pathologies, equine wound healing, musculoskeletal system and laminitis). The review also includes a table that summarizes in vitro studies on equine endothelial cells, either describing the isolation procedure or using previously isolated endothelial cells. A particular challenge of the review was that results published are fragmentary and sometimes even contradictory, raising more questions than they answer. In conclusion, angiogenesis is a major factor in several diseases frequently occurring in horses, but relatively few studies focus on angiogenesis in the horse. The challenge for the future is therefore to continue exploring new therapeutic angiogenesis strategies for horses to fill in the missing pieces of the puzzle. [ABSTRACT FROM AUTHOR]

Endometriosis (EMs) is a common disease in women of childbearing age and its pathogenesis is not yet clear. Neurofibrogenesis and angiogenesis are important mechanisms for disease progression, chronic pelvic pain, and enlargement of endometriosis lesions, and the causes are also very complex, which is likely to be closely related to the change of EMs immune microenvironment. Macrophages, an important component of the immune environment in EMs, are abnormally recruited and produce morphological and functional changes during disease development, secreting various pro - and anti -inflammatory cytokines, causing hyperexcitability of neural signals and abnormal pathway transduction, participating in the regulation of vascular endothelia growth factor (VEGF) pathway and playing an important role in neuroangiogenesis. This paper summarizes the role of macrophages in the formation of nerve fibres and blood vessels in EMs and their potential mechanisms, and provides theoretical support for targeting EMs macrophages to intervene in the inflammatory process and peripheral nerve and blood vessel generation, and provides new ideas for understanding the pathogenesis of EMs. [ABSTRACT FROM AUTHOR]

FRONTOTEMPORAL lobar degeneration, ALZHEIMER'S disease, VASCULAR dementia, CEREBRAL cortex, OCCIPITAL lobe, NEUROFIBRILLARY tangles, and CEREBRAL arteries

Aims: We observed a microvascular structure in the cerebral cortex that has not, to our knowledge, been previously described. We have termed the structure a 'raspberry', referring to its appearance under a bright‐field microscope. We hypothesized that raspberries form through angiogenesis due to some form of brain ischaemia or hypoperfusion. The aims of this study were to quantify raspberry frequency within the cerebral cortex according to diagnosis (vascular dementia, Alzheimer's disease, frontotemporal lobar degeneration and nondemented controls) and brain regions (frontal, temporal, parietal and occipital cortices, regardless of diagnosis). Materials and methods: In each of 10 age‐matched subjects per group, a 20‐mm section of the cerebral cortex was examined in haematoxylin‐and‐eosin‐stained sections of the frontal, temporal and parietal, and/or occipital lobes. Tests were performed to validate the haematoxylin‐and‐eosin‐based identification of relative differences between the groups, and to investigate inter‐rater variability. Results: Raspberry frequency was highest in subjects with vascular dementia, followed by those with frontotemporal lobar degeneration, Alzheimer's disease and last, nondemented controls. The frequency of raspberries in subjects with vascular dementia differed from that of all other groups at a statistically significant level. In the cerebral lobes, there was a statistically significant difference between the frontal and occipital cortices. Conclusions: We believe the results support the hypothesis that raspberries are a sign of angiogenesis in the adult brain. It is pertinent to discuss possible proangiogenic stimuli, including brain ischaemia (such as mild hypoperfusion due to a combination of small vessel disease and transient hypotension), neuroinflammation and protein pathology. [ABSTRACT FROM AUTHOR]

VASCULAR remodeling, THREE-dimensional imaging, and MICE

Humans, Neovascularization, Pathologic, Human Umbilical Vein Endothelial Cells, Biocompatible Materials, Tissue Scaffolds chemistry, and Tissue Engineering methods

The survival and function of transplanted tissue engineered constructs and organs require a functional vascular network. In the body, blood vessels are organized into distinct patterns that enable optimal nutrient delivery and oxygen exchange. Mimicking these same patterns in engineered tissue matrices is a critical challenge for cell and tissue transplantation. Here, we leverage bioprinting to assemble endothelial cells in to organized networks of large (>100 μm) diameter blood vessel grafts to enable spatial control of vessel formation in vivo . Acellular PEG/GelMA matrices with perfusable channels were bioprinted and laminar flow was confirmed within patterned channels, beneficial for channel endothelialization and consistent wall shear stress for endothelial maturation. Next, human umbilical vein endothelial cells (HUVECs) were seeded within the patterned channel and maintained under perfusion culture for multiple days, leading to cell-cell coordination within the construct in vitro . HUVEC and human mesenchymal stromal cells (hMSCs) were additionally added to bulk matrix to further stimulate anastomosis of our bioprinted vascular grafts in vivo. Among multiple candidate matrix designs, the greatest degree of biomaterial vascularization in vivo was seen within matrices fabricated with HUVECs and hMSCs encapsulated within the bulk matrix and HUVECs lining the walls of the patterned channels, dubbed design M-C_E. For this lead design, vasculature was detected within the endothelialized, perfusable matrix channels as early as two weeks and αSMA+ CD31+ vessels greater than 100 μm in diameter had formed by eight weeks, resulting in durable and mature vasculature. Notably, vascularization occurred within the endothelialized, bioprinted channels of the matrix, demonstrating the ability of bioprinted perfusable structures to guide vascularization patterns in vivo . The ability to influence vascular patterning in vivo can contribute to the future development of vascularized tissues and organs.

Humans, Endothelial Cells, Tumor Microenvironment, Vascular Endothelial Growth Factor A metabolism, Carcinoma, Hepatocellular drug therapy, Carcinoma, Hepatocellular pathology, Liver Neoplasms drug therapy, Liver Neoplasms pathology, Neovascularization, Pathologic, and Angiogenesis Inhibitors therapeutic use

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Angiogenesis, the process of formation of new blood vessels, is required for cancer cells to obtain nutrients and oxygen. HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth, progression, invasion, and metastasis. Current anti-angiogenic therapies target mainly tyrosine kinases, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), and are considered effective strategies for HCC, particularly advanced HCC. However, because the survival benefits conferred by these anti-angiogenic therapies are modest, new anti-angiogenic targets must be identified. Several recent studies have determined the underlying molecular mechanisms, including pro-angiogenic factors secreted by HCC cells, the tumor microenvironment, and cancer stem cells. In this review, we summarize the roles of pro-angiogenic factors; the involvement of endothelial cells, hepatic stellate cells, tumor-associated macrophages, and tumor-associated neutrophils present in the tumor microenvironment; and the regulatory influence of cancer stem cells on angiogenesis in HCC. Furthermore, we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC. A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.
Competing Interests: No potential conflicts of interest are disclosed.
(Copyright © 2023 Cancer Biology & Medicine.)

Humans, Organoids, Hydrogels, Liver, Neovascularization, Pathologic, Printing, Three-Dimensional, Tissue Scaffolds, Microfluidics, and Tissue Engineering

The vascularization of engineered tissues and organoids has remained a major unresolved challenge in regenerative medicine. While multiple approaches have been developed to vascularize in vitro tissues, it has thus far not been possible to generate sufficiently dense networks of small-scale vessels to perfuse large de novo tissues. Here, we achieve the perfusion of multi-mm 3 tissue constructs by generating networks of synthetic capillary-scale 3D vessels. Our 3D soft microfluidic strategy is uniquely enabled by a 3D-printable 2-photon-polymerizable hydrogel formulation, which allows for precise microvessel printing at scales below the diffusion limit of living tissues. We demonstrate that these large-scale engineered tissues are viable, proliferative and exhibit complex morphogenesis during long-term in-vitro culture, while avoiding hypoxia and necrosis. We show by scRNAseq and immunohistochemistry that neural differentiation is significantly accelerated in perfused neural constructs. Additionally, we illustrate the versatility of this platform by demonstrating long-term perfusion of developing neural and liver tissue. This fully synthetic vascularization platform opens the door to the generation of human tissue models at unprecedented scale and complexity.
(© 2023. The Author(s).)

Humans, Mice, Animals, Hedgehog Proteins metabolism, Zinc Finger Protein GLI1, Cells, Cultured, Neovascularization, Physiologic physiology, Endothelial Cells metabolism, Neovascularization, Pathologic, Ischemia, Receptors, G-Protein-Coupled genetics, Hyperglycemia genetics, and Diabetes Mellitus, Type 2 genetics

Impaired endothelial cell (EC)-mediated angiogenesis contributes to critical limb ischemia in diabetic patients. The sonic hedgehog (SHH) pathway participates in angiogenesis but is repressed in hyperglycemia by obscure mechanisms. We investigated the orphan G protein-coupled receptor GPR39 on SHH pathway activation in ECs and ischemia-induced angiogenesis in animals with chronic hyperglycemia. Human aortic ECs from healthy and type 2 diabetic (T2D) donors were cultured in vitro. GPR39 mRNA expression was significantly elevated in T2D. The EC proliferation, migration, and tube formation were attenuated by adenovirus-mediated GPR39 overexpression (Ad-GPR39) or GPR39 agonist TC-G-1008 in vitro. The production of proangiogenic factors was reduced by Ad-GPR39. Conversely, human ECs transfected with GPR39 siRNA or the mouse aortic ECs isolated from GPR39 global knockout (GPR39 KO ) mice displayed enhanced migration and proliferation compared with their respective controls. GPR39 suppressed the basal and ligand-dependent activation of the SHH effector GLI1, leading to attenuated EC migration. Coimmunoprecipitation revealed that the GPR39 direct binding of the suppressor of fused (SUFU), the SHH pathway endogenous inhibitor, may achieve this. Furthermore, in ECs with GPR39 knockdown, the robust GLI1 activation and EC migration were abolished by SUFU overexpression. In a chronic diabetic model of diet-induced obesity (DIO) and low-dose streptozotocin (STZ)-induced hyperglycemia, the GPR39 KO mice demonstrated a faster pace of revascularization from hind limb ischemia and lower incidence of tissue necrosis than GPR39 wild-type (GPR39 WT ) counterparts. These findings have provided a conceptual framework for developing therapeutic tools that ablate or inhibit GPR39 for ischemic tissue repair under metabolic stress.

Humans, Blood Platelets physiology, Neovascularization, Physiologic, Neovascularization, Pathologic, Neoplasms, and Lymphatic Vessels

The formation of new blood and lymphatic vessels is essential for both the development of multicellular organisms and (patho)physiological processes like wound repair and tumor growth. In the 1990s, circulating blood platelets were first postulated to regulate tumor angiogenesis by interacting with the endothelium and releasing angiogenic regulators from specialized α granules. Since then, many studies have validated the contributions of platelets to tumor angiogenesis, while uncovering novel roles for platelets in other angiogenic processes like wound resolution and retinal vascular disease. Although the majority of (lymph)angiogenesis occurs during development, platelets appear necessary for lymphatic but not vascular growth, implying their particular importance in pathological cases of adult angiogenesis. Future work is required to determine whether drugs targeting platelet production or function offer a clinically relevant tool to limit detrimental angiogenesis.
(Copyright © 2023 Cold Spring Harbor Laboratory Press; all rights reserved.)

Humans, Italy, Neoplasms pathology, and Neovascularization, Pathologic

The tumor stroma is the major factor influencing the growth of cancer. It is implicated in the regulation of tumor growth and metastatic potential and impacts the outcome of therapy. This article summarizes the fundamental contribution of the Italian scientist Pietro M. Gullino in the study of tumor stroma through the development of new experimental techniques and the characterization of novel angiogenic factors.
(© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)