Complement facilitates developmental microglial pruning of astrocyte and vascular networks

Microglia, the resident immune cell of the central nervous system, play a pivotal role in facilitating neurovascular development through mechanisms that are not fully understood. This current work resolves a previously unknown role for microglia in facilitating the developmental pruning of the astrocytic template resulting in a spatially organized retinal vascular bed. Mechanistically, our study identified that local microglial expression of complement (C)3 and C3aR is necessary for the regulation of astrocyte patterning and vascular growth during retinal development. Ablation of retinal microglia, loss of C3 or C3aR reduced developmental pruning and clearance of astrocytic bodies leading to increased astrocyte density leading to altered vascular patterning during retinal vascular development. This data demonstrates that C3/C3aR signaling is an important checkpoint required for the finetuning of vascular density during neuroretinal development.

Mechanoregulation of Vascular Endothelial Growth Factor Receptor 2 in Angiogenesis

The endothelial cells that compose the vascular system in the body display a wide range of mechanotransductive behaviors and responses to biomechanical stimuli, which act in concert to control overall blood vessel structure and function. Such mechanosensitive activities allow blood vessels to constrict, dilate, grow, or remodel as needed during development as well as normal physiological functions, and the same processes can be dysregulated in various disease states. Mechanotransduction represents cellular responses to mechanical forces, translating such factors into chemical or electrical signals which alter the activation of various cell signaling pathways. Understanding how biomechanical forces drive vascular growth in healthy and diseased tissues could create new therapeutic strategies that would either enhance or halt these processes to assist with treatments of different diseases. In the cardiovascular system, new blood vessel formation from preexisting vasculature, in a process known as angiogenesis, is driven by vascular endothelial growth factor (VEGF) binding to VEGF receptor 2 (VEGFR-2) which promotes blood vessel development. However, physical forces such as shear stress, matrix stiffness, and interstitial flow are also major drivers and effectors of angiogenesis, and new research suggests that mechanical forces may regulate VEGFR-2 phosphorylation. In fact, VEGFR-2 activation has been linked to known mechanobiological agents including ERK/MAPK, c-Src, Rho/ROCK, and YAP/TAZ. In vascular disease states, endothelial cells can be subjected to altered mechanical stimuli which affect the pathways that control angiogenesis. Both normalizing and arresting angiogenesis associated with tumor growth have been strategies for anti-cancer treatments. In the field of regenerative medicine, harnessing biomechanical regulation of angiogenesis could enhance vascularization strategies for treating a variety of cardiovascular diseases, including ischemia or permit development of novel tissue engineering scaffolds. This review will focus on the impact of VEGFR-2 mechanosignaling in endothelial cells (ECs) and its interaction with other mechanotransductive pathways, as well as presenting a discussion on the relationship between VEGFR-2 activation and biomechanical forces in the extracellular matrix (ECM) that can help treat diseases with dysfunctional vascular growth.

A review of recent advances in magnetic nanoparticle-based theranostics of glioblastoma

Rapid vascular growth, infiltrative cells and high tumor heterogenicity are some glioblastoma multiforme (GBM) characteristics, making it the most lethal form of brain cancer. Low efficacy of the conventional treatment modalities leads to rampant disease progression and a median survival of 15 months. Magnetic nanoparticles (MNPs), due to their unique physical features/inherent abilities, have emerged as a suitable theranostic platform for targeted GBM treatment. Thus, new strategies are being designed to enhance the efficiency of existing therapeutic techniques such as chemotherapy, radiotherapy, and so on, using MNPs. Herein, the limitations of the current therapeutic strategies, the role of MNPs in mitigating those inadequacies, recent advances in the MNP-based theranostics of GBM and possible future directions are discussed.

Regulatory proteins in placental angiogenesis

The vasculature of the placenta plays a crucial role during the course of pregnancy in order to maintain the growing need of the fetus. Abnormal placental structure and function significantly increase the risk of stillbirth. Various growth factors and cytokines play an important role in the vasculogenesis and angiogenesis of placenta. These processes are stimulated by various pro-angiogenic factors. The activities of these factors are also stimulated by hypoxia. In some of the physiological phenomenon like ovulation, embryogenesis as well as in wound healing intense blood vessel growth can be seen similar to that seen in placenta. Therefore, factors that induce and maintain placental vascular growth and function are of considerable developmental and clinical significance. The total arterial architecture may also depend upon the pro-angiogenic factors. Hormones and other growth factors are other contributors of this vasculogenesis and angiogenesis. Any dysfunction of factors can lead to foetal hypoxia and related complications. This review describes the major growth factors and their significant role in vasculogenesis and angiogenesis of placenta.

Proangiogenic Effect of Affinin and an Ethanolic Extract from Heliopsis longipes Roots: Ex Vivo and In Vivo Evidence

Angiogenesis, the formation of new blood vessels, underlies tissue development and repair. Some medicinal plant-derived compounds can modulate the angiogenic response. Heliopsis longipes, a Mexican medicinal plant, is widely used because of its effects on pain and inflammation. The main bioactive phytochemicals from H. longipes roots are alkamides, where affinin is the most abundant. Scientific studies show various medical effects of organic extracts of H. longipes roots and affinin that share some molecular pathways with the angiogenesis process, with the vasodilation mechanism of action being the most recent. This study investigates whether pure affinin and the ethanolic extract from Heliopsis longipes roots (HLEE) promote angiogenesis. Using the aortic ring rat assay (ex vivo method) and the direct in vivo angiogenesis assay, where angioreactors were implanted in CD1 female mice, showed that affinin and the HLEE increased vascular growth in a dose-dependent manner in both bioassays. This is the first study showing the proangiogenic effect of H. longipes. Further studies should focus on the mechanism of action and its possible therapeutic use in diseases characterized by insufficient angiogenesis.

MiRNAs as Anti-Angiogenic Adjuvant Therapy in Cancer: Synopsis and Potential

Angiogenesis is a key mechanism for tumor growth and metastasis and has been a therapeutic target for anti-cancer treatments. Intensive vascular growth is concomitant with the rapidly proliferating tumor cell population and tumor outgrowth. Current angiogenesis inhibitors targeting either one or a few pro-angiogenic factors or a range of downstream signaling molecules provide clinical benefit, but not without significant side effects. miRNAs are important post-transcriptional regulators of gene expression, and their dysregulation has been associated with tumor progression, metastasis, resistance, and the promotion of tumor-induced angiogenesis. In this mini-review, we provide a brief overview of the current anti-angiogenic approaches, their molecular targets, and side effects, as well as discuss existing literature on the role of miRNAs in angiogenesis. As we highlight specific miRNAs, based on their activity on endothelial or cancer cells, we discuss their potential for anti-angiogenic targeting in cancer as adjuvant therapy and the importance of angiogenesis being evaluated in such combinatorial approaches.

MODERN DIAGNOSIS OF PLACENTAL DYSFUNCTION AND ITS COMPLICATIONS

The aim of the study was to improve the modern diagnosis of placental dysfunction and its complications. Materials and methods. The study involved a prospective survey of 70 pregnant women divided into the main group (pregnant women with placental dysfunction) (n = 50) and the control group (n = 20). The main group was divided into subgroups of pregnant women with placental dysfunction and fetal growth retardation (n = 30) and pregnant women with placental dysfunction without fetal growth retardation (n = 20). The control group comprised 20 pregnant women with physiological gestation. Apart from history taking, the study comprised obstetric and general clinical examination, evaluation of endothelium- dependent vasodilation, serum concentrations of soluble forms of vascular and platelet- endothelial molecules of cell adhesion 1, indicators of athrombogenicity of the vascular growth wall, uterine-placental-fetal blood circulation, pathomorphological and histometric examination of the placenta. Results. Based on the obtained clinical-morphological and endotheliotropic criteria, a personalized clinical algorithm for managing pregnant women with placental dysfunction was developed and implemented. Conclusions. Assessment of pregnancy results in a prospective clinical study showed that the proposed algorithm for personalization of the risk of perinatal abnormalities not only helped to avoid antenatal mortality, but also to prevent intranatal and early neonatal losses in patients with placental dysfunction and fetal growth retardation.

Angiogenesis is critical for the regenerative effects of exercise.

Enhancing axon regeneration is a major focus of nerve injury research, and the quality of the surgical nerve repair plays a large role in the aggregate success of nerve regeneration. Additionally, exercise is known to promote successful axon regeneration after surgical nerve repair. In this study, we asked how exercise-induced nerve regeneration is affected when a transected nerve is repaired with or without fibrin glue. Fibrin glue repaired nerves exhibited greater vasculature within the tissue bridge compared to nerves that were intrinsically repaired. Fibrin glue repaired nerves also exhibited more robust axon regeneration after exercise compared to nerves that were not repaired with fibrin glue. When angiogenesis of the tissue bridge was prevented, exercise was unable to enhance regeneration despite the presence of fibrin glue. These findings suggest that the biological properties of fibrin glue enhance angiogenesis within the repair site, and a vascularized bridge is required for enhanced axon elongation with exercise. The combination of fibrin glue repair and exercise resulted in notable differences in vascular growth, axon elongation, neuromuscular junction reinnervation, and functional recovery. Fibrin glue should be considered as an adjuvant for nerve repair to enhance the subsequent efficacy of activity- and physical therapy-based treatment interventions.

Integration of vascular progenitors into functional blood vessels represents a novel mechanism of vascular growth

During embryogenesis, the initial vascular network is thought to form by the process of vasculogenesis, or the specification of vascular progenitors de novo. After the initial blood circulation has been established, the majority of later-forming vessels are thought to arise by angiogenesis from the already established vasculature. Here we show that new vascular progenitors in zebrafish embryos contribute to functional vasculature even after blood circulation has been established. Based on the expression analysis of early vascular progenitor markers etv2 and tal1, we characterized a novel site of late vasculogenesis (termed secondary vascular field, SVF), located bilaterally along the yolk extension. Using time-lapse imaging of etv2 reporter lines, we show that SVF cells migrate and incorporate into functional blood vessels and contribute to the formation of the posterior cardinal vein and subintestinal vasculature, suggesting a novel mode of vascular growth. We further demonstrate that SVF cells participate in vascular recovery after chemical ablation of vascular endothelial cells. Inducible inhibition of etv2 function prevented SVF cell differentiation and resulted in the defective formation of subintestinal vasculature. In addition, we performed single-cell RNA-seq analysis to identify the transcriptional profile of SVF cells, which demonstrated similarities and differences between the transcriptomes of SVF cells and early vascular progenitors. Our results characterize a novel mechanism of how new vascular progenitors incorporate into established vasculature and revise our understanding of basic mechanisms that regulate vascular development.

Estimation of the level of endothelial factor of vascular growth and monocytic chemoattractant in children cerebral palsy

Objective. The aim of this article is to assess the role of vascular endothelial growth factor and monocytic chemoattractant in the development of cerebral palsy in children. Materials and methods. Examination of 77 children with different clinical forms of infantile cerebral palsy in the age group from 1 to 16 years was carried out. The content of monocyte chemoattractant (MCP) and vascular growth factor (VEGF) was determined in different forms of cerebral palsy. The obtained data were processed statistically. Results. The analysis of the obtained data revealed a significant increase in the indicators of monocytic chemoattractant and vascular growth factor in children with infantile cerebral palsy compared with healthy children. There were no significant differences between the indicators of MCP and VEGF in children with cerebral palsy and comorbid pathology and children with cerebral palsy without concomitant pathology. Conclusion. The authors of the presented analysis conclude that the determination of monocytic chemoattractant and vascular growth factor has a high diagnostic value for identifying a predisposition to the development of cerebral palsy. Timely detection of an increase in the level of these factors provides a broader prospective for early diagnosis of the disease and for the early implementation of rehabilitation measures accordingly.