Interactions In Angiogenesis Research Articles

The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is a leading cause of vision impairment and blindness in premature infants. Oxidative stress is implicated in its pathophysiology. NADPH oxidase (NOX), a major enzyme responsible for reactive oxygen species (ROS) generation in endothelial cells, has been studied for its involvement in physiologic and pathologic angiogenesis. Erythropoietin (EPO) has gained interest recently due to its tissue protective and angiogenic effects, and it has been shown to act as an antioxidant. In this review, we summarize studies performed over the last five years regarding the role of various NOXs in physiologic and pathologic angiogenesis. We also discuss the effect of EPO in tissue and vasoprotection, and the intersection of EPO and NOX-mediated oxidative stress in angiogenesis and the pathophysiology of ROP.

A regulatory microRNA network controls endothelial cell phenotypic switch during sprouting angiogenesis.

Angiogenesis requires the temporal coordination of the proliferation and the migration of endothelial cells. Here, we investigated the regulatory role of microRNAs (miRNAs) in harmonizing angiogenesis processes in a three-dimensional in vitro model. We described a microRNA network which contributes to the observed down- and upregulation of proliferative and migratory genes, respectively. Global analysis of miRNA-target gene interactions identified two sub-network modules, the first organized in upregulated miRNAs connected with downregulated target genes and the second with opposite features. miR-424-5p and miR-29a-3p were selected for the network validation. Gain- and loss-of-function approaches targeting these microRNAs impaired angiogenesis, suggesting that these modules are instrumental to the temporal coordination of endothelial migration and proliferation. Interestingly, miR-29a-3p and its targets belong to a selective biomarker that is able to identify colorectal cancer patients who are responding to anti-angiogenic treatments. Our results provide a view of higher-order interactions in angiogenesis that has potential to provide diagnostic and therapeutic insights.

Engineering of an angiogenic niche by perfusion culture of adipose-derived stromal vascular fraction cells

In vitro recapitulation of an organotypic stromal environment, enabling efficient angiogenesis, is crucial to investigate and possibly improve vascularization in regenerative medicine. Our study aims at engineering the complexity of a vascular milieu including multiple cell-types, a stromal extracellular matrix (ECM), and molecular signals. For this purpose, the human adipose stromal vascular fraction (SVF), composed of a heterogeneous mix of pericytes, endothelial/stromal progenitor cells, was cultured under direct perfusion flow on three-dimensional (3D) collagen scaffolds. Perfusion culture of SVF-cells reproducibly promoted in vitro the early formation of a capillary-like network, embedded within an ECM backbone, and the release of numerous pro-angiogenic factors. Compared to static cultures, perfusion-based engineered constructs were more rapidly vascularized and supported a superior survival of delivered cells upon in vivo ectopic implantation. This was likely mediated by pericytes, whose number was significantly higher (4.5-fold) under perfusion and whose targeted depletion resulted in lower efficiency of vascularization, with an increased host foreign body reaction. 3D-perfusion culture of SVF-cells leads to the engineering of a specialized milieu, here defined as an angiogenic niche. This system could serve as a model to investigate multi-cellular interactions in angiogenesis, and as a module supporting increased grafted cell survival in regenerative medicine.

Cell-based modeling of cell-matrix interactions in angiogenesis

The self-organization of endothelial cells into blood vessel networks and sprouts can be studied using computational, cell-based models. These take as input the behavior of individual, endothelial cells, as observed in experiments, and gives as output the resulting, collective behavior, i.e. the formation of shapes and tissue structures. Many cell-based models ignore the extracellular matrix, i.e., the fibrous or homogeneous materials that surround cells and gives tissue structural support. In this extended abstract, we highlight two approaches that we have taken to explore the role of the extracellular matrix in our cellular Potts models of blood vessel formation (angiogenesis): first we discuss a model considering chemical endothelial cell-matrix interactions, then we discuss a model that include mechanical cell-matrix interactions. We end by discussing some potential new directions.

Constructing the angiome: a global angiogenesis protein interaction network

Angiogenesis is the formation of new blood vessels from pre-existing microvessels. Excessive and insufficient angiogenesis have been associated with many diseases including cancer, age-related macular degeneration, ischemic heart, brain, and skeletal muscle diseases. A comprehensive understanding of angiogenesis regulatory processes is needed to improve treatment of these diseases. To identify proteins related to angiogenesis, we developed a novel integrative framework for diverse sources of high-throughput data. The system, called GeneHits, was used to expand on known angiogenesis pathways to construct the angiome, a protein-protein interaction network for angiogenesis. The network consists of 478 proteins and 1,488 interactions. The network was validated through cross validation and analysis of five gene expression datasets from in vitro angiogenesis assays. We calculated the topological properties of the angiome. We analyzed the functional enrichment of angiogenesis-annotated and associated proteins. We also constructed an extended angiome with 1,233 proteins and 5,726 interactions to derive a more complete map of protein-protein interactions in angiogenesis. Finally, the extended angiome was used to identify growth factor signaling networks that drive angiogenesis and antiangiogenic signaling networks. The results of this analysis can be used to identify genes and proteins in different disease conditions and putative targets for therapeutic interventions as high-ranked candidates for experimental validation.

Maternal Heme Oxygenase 1 Regulates Placental Vasculature Development via Angiogenic Factors in Mice1

The placental vasculature is critical for nutrient, gas, and waste exchange between the maternal and fetal systems. Its development depends on the proper expression and interaction of angiogenesis and associated growth factors. Heme oxygenase (HMOX), the enzyme for heme degradation, plays a role in angiogenesis and is highly expressed in the placenta. To evaluate the role of maternal HMOX1, the inducible HMOX isozyme, on placental vasculature formation, mice with a partial deficiency in Hmox1 (Hmox1(+/-)) were used. Three-dimensional images of placental vasculatures as well as spiral arteries from Hmox1(+/+) or Hmox1(+/-) placentas were created by vascular corrosion casting technique and imaged by micro-computerized tomography (microCT). The structures and morphologies of fetomaternal interfaces were observed by histological staining and the ultrastructure of uterine natural killer (uNK) cells, a major regulator in spiral artery remodeling, was analyzed by transmission electron microscopy. A group of growth factors and angiogenic factors from the decidua/mesometrial lymphoid aggregate of pregnancy (MLAp) as well as labyrinth regions were quantified using an angiogenesis PCR array kit and compared between Hmox1(+/+) or Hmox1(+/-) placentas. In conclusion, a partial deficiency of maternal Hmox1 resulted in the malformation of fetomaternal interface, insufficiency of spiral artery remodeling, and alteration of uNK cell differentiation and maturation. These changes were independent of the fetal genotype, but relied on the maternal HMOX1 level, which determined the balance of expression levels of pro- and antiangiogenic factors in the decidua/MLAp region. These results implied that Hmox1 polymorphisms among the human population might contribute to some unexplained cases of pregnancy disorders, such as fetal growth retardation and preeclampsia.

Application of magnetic force‐based cell patterning for controlling cell–cell interactions in angiogenesis

To investigate the effects of cell-cell interactions on cellular function, the microenvironment surrounding cells should be precisely controlled. Here, we describe a cell patterning technique, which utilizes magnetic force and magnetite nanoparticles. This method was used to develop cell culture arrays for investigation of cell behaviors in angiogenesis. Pin holder devices that contain more than 6,000 pillars on the surface are used for fabricating the cell culture arrays by setting it on a magnet. The magnetically labeled cells were arranged by magnetic distribution. When the human umbilical vein endothelial cells are arranged at 250 microm intervals (5.9 cells/spot), the cells spread toward other cell cluster on adjacent spots in 4.5 h, and formed cord-like structures in 8.5 h. It was shown that cell-cell interactions were successfully investigated using magnetic cell arrangement.

Endothelial cell_collagen interactions in angiogenesis

Endothelial cell_collagen interactions in angiogenesis

Targeting angiogenesis versus myogenesis with cardiac cell therapy

Considerable hope has been vested in cell therapy strategies designed to augment the endogenous neovascularization response to obstructive coronary artery disease, and to replace cardiomyocyte loss caused by myocardial infarction. Conceptually, the relative importance of targeting angiogenesis versus myogenesis in this scheme will vary depending on the clinical context (the predominance of ischemia versus ventricular dysfunction and scarring). Although the evidence so far is encouraging, whether these processes can be effectively targeted in a selective fashion with cell therapy is still unclear. Intriguingly, data are now emerging suggesting that the beneficial effects of cardiac cell therapies in a variety of clinical settings may be accounted for by a greater interaction of angiogenesis, myocardial salvage and myogenesis than heretofore appreciated, and through mechanisms that may include both cellular and paracrine effects. Greater understanding of these mechanisms should accelerate the development of effective cell therapies for the growing number of patients with advanced, and in many cases ‘no-option’, cardiovascular disease. Possible clinical targets for angiogenic and myogenic cardiac cell therapy, the scientific rationale for this therapeutic approach and future directions in this field are discussed here.

Endothelial-pericyte interactions in angiogenesis.

It takes two to make blood vessels-endothelial cells and pericytes. While the endothelial cells are the better characterized of the two, pericytes are now coming into focus as important regulators of angiogenesis and blood vessel function, and as potential drug targets. However, pericytes are still surrounded by much controversy. They are difficult to define, they constitute a heterogeneous population of cells, and their ontogeny is not well understood. They are plastic and have the capacity to differentiate into other mesenchymal cell types, such as smooth muscle cells, fibroblasts and osteoblasts. Recent interest in pericytes also stems from their potential involvement in diseases such as diabetic microangiopathy, tissue fibrosis, cancer, atherosclerosis and Alzheimer's disease. The present review focuses on the role of pericytes in physiological angiogenesis. The currently favored view states that the initial endothelial tubes form without pericyte contact, and that subsequent acquisition of pericyte coverage leads to vessel remodeling, maturation and stabilization. Improved means of identifying and visualizing pericytes now challenge this view and show that high numbers of pericytes invest in actively sprouting and remodeling vessels. Genetic data demonstrate the critical importance of pericytes for vascular morphogenesis and function, and imply specific roles for the cell type in various aspects of angiogenesis.