Secreted frizzled-related proteins in angiogenesis: molecular mechanisms and clinical implications

Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?

The angiogenic cascade is getting increasingly complex. A few years ago, vasculogenesis and angiogenesis were considered as the primary mechanisms leading to the formation of new blood vessels. The original definition of vasculogenesis denotes the formation of a primary embryonic vascular network from in situ differentiating angioblastic cells.1 In contrast, angiogenesis primarily referred to the sprouting of blood vessels from preexisting vessels.1 Recent advances in the identification of molecules that regulate angiogenesis and vascular remodeling have shown that the simplistic model of an invading capillary sprout is not sufficient to appreciate the whole spectrum of morphogenic events that are required to form a neovascular network (Figure 1).1–3 Undoubtedly, vascular endothelial growth factor (VEGF) acts at an early point in the hierarchical order of morphogenic events and probably fulfills all criteria to be considered as a master switch of the angiogenic cascade. In contrast, the angiopoietins and their receptor Tie-2 as well as the ephrins and their corresponding Eph receptors appear to act at a somewhat later stage of neovessel formation. These molecules orchestrate a number of related, yet functionally and molecularly not well understood, processes such as vessel assembly (network formation and formation of anastomoses), vessel maturation (recruitment of mural cells [pericytes and smooth muscle cells], and extracellular matrix assembly, pruning of the primary vascular bed), and acquisition of vessel identity (formation of arteries, capillaries, and veins)3,4 (Figure 2). Lastly, the mechanisms of organotypic differentiation of the vascular tree (continuous endothelium, discontinuous endothelium, fenestrated endothelium) are not at all understood and the first molecules that govern subpopulation-specific vascular growth and differentiation are just being uncovered.5,6 Figure 1. Change of paradigm. From sprouting angiogenesis to vascular morphogenesis. Basement membrane degradation, directed endothelial cell migration, and proliferation (left) were considered as the primary mechanisms of angiogenesis. …

Angiogenesis and vasculogenesis: Inducing the growth of new blood vessels and wound healing by stimulation of bone marrow–derived progenitor cell mobilization and homing

Although Nogo-A has been identified in the central nervous system as an inhibitor of axonal regeneration, the peripheral roles of Nogo isoforms remain virtually unknown. Here, using a proteomic analysis to identify proteins enriched in caveolae and/or lipid rafts (CEM/LR), we show that Nogo-B is highly expressed in cultured endothelial and smooth muscle cells, as well as in intact blood vessels. The N terminus of Nogo-B promotes the migration of endothelial cells but inhibits the migration of vascular smooth muscle (VSM) cells, processes necessary for vascular remodeling. Vascular injury in Nogo-A/B-deficient mice promotes exaggerated neointimal proliferation, and adenoviral-mediated gene transfer of Nogo-B rescues the abnormal vascular expansion in those knockout mice. Our discovery that Nogo-B is a regulator of vascular homeostasis and remodeling broadens the functional scope of this family of proteins.

Circulating Angiogenic Precursors in Idiopathic Pulmonary Arterial Hypertension

What is the role of SFRP2 in endometriosis? SFRP2 acts as a canonical WNT/CTNNB1 signaling agonist in endometriosis, regulating endometriosis lesion growth and indicating endometriosis lesion borders together with CTNNB1 (also known as beta catenin). Endometriosis is a common, chronic disease that affects women of reproductive age, causing pain and infertility, and has significant economic impact on national health systems. Despite extensive research, the pathogenesis of endometriosis is poorly understood, and targeted medical treatments are lacking. WNT signaling is dysregulated in various human diseases, but its role in extraovarian endometriosis has not been fully elucidated. We evaluated the significance of WNT signaling, and especially secreted frizzled-related protein 2 (SFRP2), in extraovarian endometriosis, including peritoneal and deep lesions. The study design was based on a cohort of clinical samples collected by laparoscopy or curettage and questionnaire data from healthy controls and endometriosis patients. Global gene expression analysis in human endometrium (n = 104) and endometriosis (n = 177) specimens from 47 healthy controls and 103 endometriosis patients was followed by bioinformatics and supportive qPCR analyses. Immunohistochemistry, Western blotting, primary cell culture and siRNA knockdown approaches were used to validate the findings. Among the 220 WNT signaling and CTNNB1 target genes analysed, 184 genes showed differential expression in extraovarian endometriosis (P < 0.05) compared with endometrium tissue, including SFRP2 and CTNNB1. Menstrual cycle-dependent regulation of WNT genes observed in the endometrium was lost in endometriosis lesions, as shown by hierarchical clustering. Immunohistochemical analysis indicated that SFRP2 and CTNNB1 are novel endometriosis lesion border markers, complementing immunostaining for the known marker CD10 (also known as MME). SFRP2 and CTNNB1 localized similarly in both the epithelium and stroma of extraovarian endometriosis tissue, and interestingly, both also indicated an additional distant lesion border, suggesting that WNT signaling is altered in the endometriosis stroma beyond the primary border indicated by the known marker CD10. SFRP2 expression was positively associated with pain symptoms experienced by patients (P < 0.05), and functional loss of SFRP2 in extraovarian endometriosis primary cell cultures resulted in decreased cell proliferation (P < 0.05) associated with reduced CTNNB1 protein expression (P = 0.05). SFRP2 and CTNNB1 improved extraovarian endometriosis lesion border detection in a relatively small cohort (n = 20), although larger studies with different endometriosis subtypes in variable cycle phases and under hormonal medication are required. The highly expressed SFRP2 and CTNNB1 improve endometriosis lesion border detection, which can have clinical implications for better visualization of endometriosis lesions over CD10. Furthermore, SFRP2 acts as a canonical WNT/CTNNB1 signaling agonist in endometriosis and positively regulates endometriosis lesion growth, suggesting that the WNT pathway may be an important therapeutic target for endometriosis. This study was funded by the Academy of Finland and by Tekes: Finnish Funding Agency for Innovation. The authors have no conflict of interest to declare.

Neuroinflammation is a common feature of many neurodegenerative diseases. It fosters a dysfunctional neuron–microglia–astrocyte crosstalk that, in turn, maintains microglial cells in a perniciously reactive state that often enhances neuronal damage. The molecular components that mediate this critical communication are not fully explored. Here, we show that secreted frizzled‐related protein 1 (SFRP1), a multifunctional regulator of cell‐to‐cell communication, is part of the cellular crosstalk underlying neuroinflammation. In mouse models of acute and chronic neuroinflammation, SFRP1, largely astrocyte‐derived, promotes and sustains microglial activation, and thus a chronic inflammatory state. SFRP1 promotes the upregulation of components of the hypoxia‐induced factor‐dependent inflammatory pathway and, to a lower extent, of those downstream of the nuclear factor‐kappa B. We thus propose that SFRP1 acts as an astrocyte‐to‐microglia amplifier of neuroinflammation, representing a potential valuable therapeutic target for counteracting the harmful effect of chronic inflammation in several neurodegenerative diseases.

Mechanistic insight into lysyl oxidase in vascular remodeling and angiogenesis

Angiogenesis/tumor hypoxia: new treatment options?

Angiogenesis, the formation of new blood vessels from preexisting ones, is a critical component of various pathologies such as tumor progression, rheumatoid arthritis, and retinopathies. Vascular endothelial growth factor (VEGF) is a mitogenic and chimiotactic factor capable of inducing angiogenesis through the activation of its receptors, fetal liver kinase-1 (Flk-1) and fms-like tyrosine kinase-1 (Flt-1), expressed on endothelial cells. The purpose of the present study was to assess if a treatment with antisense (AS) oligonucleotides directed against VEGF receptors Flk-1 or Flt-1 mRNA could prevent VEGF-mediated angiogenesis. With the use of miniosmotic pumps, phosphate-buffered saline, VEGF, or VEGF combined with AS-Flk-1, AS-Flt-1, or AS-scrambled oligonucleotides were released in mouse testis for 14 days. VEGF (1, 2.5, and 5 microg) increased the formation of new capillary blood vessels by 236, 246, and 287%, respectively. The combination of AS-Flk-1 or AS-Flt-1 (200 microg) to VEGF (2.5 microg) reduced by 87 and 85% the formation of new blood vessels, respectively, and the expression of their corresponding proteins. These data demonstrate the therapeutical potential of AS-Flk-1 or AS-Flt-1 to prevent VEGF-mediated angiogenesis in vivo.

Angiogenesis, the process of formation of new blood vessels from pre-existing vasculature, is essential for tumor growth and metastasis. Anti-angiogenic treatment targeting vascular endothelial growth factor (VEGF) signaling is a powerful tool to combat tumor growth; however, anti-tumor angiogenesis therapy has shown limited efficacy, with survival benefits ranging from only a few weeks to months. Compensation by upregulation of complementary growth factors and switches to different modes of vascularization have made these types of therapies less effective. Recent evidence suggests that targeting specific players in endothelial metabolism is a valuable therapeutic strategy against tumor angiogenesis. Although it is clear that metabolism can modulate the translational machinery, the reciprocal relationship between metabolism and mRNA translational control during tumor angiogenesis is not fully understood. In this review, we explore emerging examples of how endothelial cell metabolism affects mRNA translation during the formation of blood vessels. A deeper comprehension of these mechanisms could lead to the development of innovative therapeutic strategies for both physiological and pathological angiogenesis.

The vascular system is essential for embryogenesis, healing, and homeostasis. Dysfunction or deregulated blood vessel function contributes to multiple diseases, including diabetic retinopathy, cancer, hypertension, or vascular malformations. A balance between the formation of new blood vessels, vascular remodeling, and vessel quiescence is fundamental for tissue growth and function. Whilst the major mechanisms contributing to the formation of new blood vessels have been well explored in recent years, vascular remodeling and quiescence remain poorly understood. In this review, we highlight the cellular and molecular mechanisms responsible for vessel remodeling and quiescence during angiogenesis. We further underline how impaired remodeling and/or destabilization of vessel networks can contribute to vascular pathologies. Finally, we speculate how addressing the molecular mechanisms of vascular remodeling and stabilization could help to treat vascular-related disorders.

Several steps in the formation of new blood vessels have been elucidated. Among these steps are breakdown of surrounding extracellular matrix, migration of vascular endothelial cell to form an advancing new blood vessel sprout, and endothelial cells proliferation at the base of the sprout. Two other important events in the process of new blood vessel formation have yet to receive much attention. These steps are formation of the new blood vessel lumen and maintenance of the new blood vessels. The importance of the maintenance of new blood vessels becomes apparent when one realizes that new blood vessels regress rapidly once the stimulating factor or factors are removed. We will therefore present two sets of studies. The first set of studies relates to the in vitro formation of capillary like structures by vascular-endothelial cells. The mechanism of lumen formation in this model is described. It is not clear whether this mechanism of lumen formation occurs in vivo. The second set of studies elucidates some of the factors that may play a role in the maintenance of new blood vessels and their subsequent regression upon removal of the angiogenic stimulators.

Angiogenesis is the formation of new capillaries from pre-existing vasculature, which plays a critical role in the pathogenesis of several inflammatory autoimmune diseases such as rheumatoid arthritis (RA), spondyloarthropathies, psoriasis, systemic lupus erythematosus, systemic sclerosis, and atherosclerosis. In RA, excessive migration of circulating leukocytes into the inflamed joint necessitates formation of new blood vessels to provide nutrients and oxygen to the hypertrophic joint. The dominance of the pro-angiogenic factors over the endogenous angiostatic mediators triggers angiogenesis. In this review article, we highlight the underlying mechanisms by which cells present in the RA synovial tissue are modulated to secrete pro-angiogenic factors. We focus on the significance of pro-angiogenic factors such as growth factors, hypoxia-inducible factors, cytokines, chemokines, matrix metalloproteinases,and adhesion molecules on RA pathogenesis. As pro-angiogenic factors are primarily produced from RA synovial tissue macrophages and fibroblasts, we emphasize the key role of RA synovial tissue lining layer in maintaining synovitis through neovascularization. Lastly, we summarize the specific approaches utilized to target angiogenesis. We conclude that the formation of new blood vessels plays an indispensable role in RA progression. However, since the function of several pro-angiogenic mediators is cross regulated, discovering novel approaches to target multiple cascades or selecting an upstream cascade that impairs the activity of a number of pro-angiogenic factors may provide a promising strategy for RA therapy.

A New Mechanism for Pillar Formation during Tumor-Induced Intussusceptive Angiogenesis: Inverse Sprouting