CCRL2 Modulates Physiological and Pathological Angiogenesis During Retinal Development

Chemerin is a multifunctional protein involved in the regulation of inflammation, metabolism, and tumorigenesis. It binds to three receptors, CMKLR1, GPR1 and CCRL2. CMKLR1 is a fully functional receptor mediating most of the known activities of chemerin. CCRL2 does not seem to couple to any intracellular signaling pathway and is presently considered as an atypical receptor able to present the protein to cells expressing CMKLR1. CCRL2 is expressed by many cell types including leukocyte subsets and endothelial cells, and its expression is strongly upregulated by inflammatory stimuli. We recently reported that chemerin can negatively regulate the angiogenesis process, including during the development of the vascular network in mouse retina. The role of CCRL2 in angiogenesis was unexplored so far. In the present work, we demonstrate that mice lacking CCRL2 exhibit a lower density of vessels in the developing retina and this phenotype persists in adulthood, in a CMKLR1-dependent manner. Vascular sprouting was not affected, while vessel pruning, and endothelial cell apoptosis were increased. Pathological angiogenesis was also reduced in CCRL2-/- mice in a model of oxygen-induced retinopathy. The phenotype closely mimics that of mice overexpressing chemerin, and the concentration of chemerin was found elevated in the blood of newborn mice, when the retinal vasculature develops. CCRL2 appears therefore to regulate the distribution and concentration of chemerin in organs, regulating thereby its bioactivity.

Psoriasis and pathological angiogenesis: pathogenetic signifcance and therapeutic perspectives

The literature review presents data on the role of pathological angiogenesis in the development of psoriasis. Several recent studies have shown, in addition to cytokine imbalance and activation of the T-cell link of immunity, an important pathogenetic link is pathological vascularization. Vascular changes in the dermis appear before clinically visible skin manifestations and can persist for a long time after treatment, as well as the phenomena of neoangigenesis in the synovial membrane and enthesises contribute to the chronicization of inflammatory process in psoriatic arthritis. The article presents an overview of the modern literature on the main regulator of angiogenesis – vascular endothelial growth factor, its role in the pathogenesis of psoriasis and possible therapeutic prospects.

Screening of a Library for Factor VIIa Inhibitors

Background: As an alternative to the anticoagulant’s strategy using direct or indirect anti-Xa drugs, considering other targets upstream in the coagulation cascade such as anti-Factor VIIa could represent an effective and safer strategy in coagulation and pathological angiogenesis. Objective: The objective of the study was to assess a high technology methodology composed of virtual screening, anticoagulant, and anti-angiogenesis assays to identify potent small-molecule FVIIa inhibitors. Methods: Chemical databanks were screened to select molecules bearing functional groups that could fit into the active site of FVIIa, which were then tested. Ligands assigned with the lowest scores were retained and then biologically assessed. Results: From the 500 molecules considered, 8 chemical structures revealed to be effective compounds in vitro and to inhibit angiogenesis in the chick chorioallantoic membrane (CAM) model. Conclusion: New potent small-molecule FVIIa inhibitors have been identified; further biochemical and chemical developments would be investigated directly from the selected scaffolds.

AS1411 Nucleolin-Specific Binding Aptamers Reduce Pathological Angiogenesis through Inhibition of Nucleolin Phosphorylation

Proliferative retinopathies produces an irreversible type of blindness affecting working age and pediatric population of industrialized countries. Despite the good results of anti-VEGF therapy, intraocular and systemic complications are often associated after its intravitreal use, hence novel therapeutic approaches are needed. The aim of the present study is to test the effect of the AS1411, an antiangiogenic nucleolin-binding aptamer, using in vivo, ex vivo and in vitro models of angiogenesis and propose a mechanistic insight. Our results showed that AS1411 significantly inhibited retinal neovascularization in the oxygen induced retinopathy (OIR) in vivo model, as well as inhibited branch formation in the rat aortic ex vivo assay, and, significantly reduced proliferation, cell migration and tube formation in the HUVEC in vitro model. Importantly, phosphorylated NCL protein was significantly abolished in HUVEC in the presence of AS1411 without affecting NFκB phosphorylation and -21 and 221-angiomiRs, suggesting that the antiangiogenic properties of this molecule are partially mediated by a down regulation in NCL phosphorylation. In sum, this new research further supports the NCL role in the molecular etiology of pathological angiogenesis and identifies AS1411 as a novel anti-angiogenic treatment.

A Systematic Review on the Role of Adrenergic Receptors in Angiogenesis Regulation in Health and Disease

Angiogenesis is essential during development or when tissue restoration and oxygenation is required. Limited or excessive formation of blood vessels is a hallmark of several pathologies, and many angiogenesis-related pathways are being studied to highlight potential targets for effective angiogenesis-stimulating or inhibiting therapeutic approaches. A few studies point to the adrenergic system as a significant regulator of angiogenesis, directly or indirectly. Functional adrenergic receptors are expressed on endothelial cells and affect their response to the adrenergic system. The latter can also upregulate the release of growth factors by mural cells of the vessel wall, blood cells or cancer cells, thus subsequently affecting endothelial cell functions and angiogenesis. In the present study we summarize up-to-date literature on the known effects of the adrenergic receptors on physiological and pathological angiogenesis.

Increased Plasma GDF15 Is Associated with Altered Levels of Soluble VEGF Receptors 1 and 2 in Symptomatic Multiple Myeloma

<b><i>Introduction:</i></b> In multiple myeloma, there is an increase in bone marrow microvascular density and enhanced renal lymphangiogenesis. Increased levels of the proangiogenic protein growth differentiation factor-15 (GDF15) have previously been reported to be associated with poor prognosis in myeloma. A possible association between GDF15 and the soluble forms of vascular endothelial growth factor receptors (sVEGFR) 1 and 2 has not yet been investigated, and a role for these receptors in pathological angiogenesis in myeloma is still to be defined. <b><i>Methods:</i></b> Plasma levels of GDF15 and sVEGFR1 and 2 were determined by ELISA in patients with smouldering multiple myeloma (sMM), patients with symptomatic multiple myeloma (abbreviated as MM), and healthy controls. The levels were compared between the three groups, and correlation coefficients were calculated, as were Kaplan-Meier curves for GDF15 and sVEGFR1 and sVEGFR2. <b><i>Results:</i></b> Levels of GDF15 were significantly higher in MM than in both patients with sMM and controls. A gradual decrease in mean sVEGFR1 concentration was observed, with MM &#x3e; sMM &#x3e; controls. Mean sVEGFR2 was lower in patients with MM than in controls. There was a positive correlation between GDF15 and sVEGFR1, and GDF15 correlated negatively with sVEGFR2. High GDF15 (&#x3e;3 ng/mL) was associated with poor prognosis. <b><i>Conclusion:</i></b> In multiple myeloma, increased expression of GDF15 correlates positively with sVEGFR1 and negatively with sVEGFR2. It is possible that the altered levels of sVEGFR1 and 2 contribute to the increased angio- and lymphangiogenesis observed in myeloma.

Selective Targeting and Tissue Penetration to the Retina by a Systemically Administered Vascular Homing Peptide in Oxygen Induced Retinopathy (OIR)

Pathological angiogenesis is the hallmark of ischemic retinal diseases among them retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Oxygen-induced retinopathy (OIR) is a pure hypoxia-driven angiogenesis model and a widely used model for ischemic retinopathies. We explored whether the vascular homing peptide CAR (CARSKNKDC) which recognizes angiogenic blood vessels can be used to target the retina in OIR. We were able to demonstrate that the systemically administered CAR vascular homing peptide homed selectively to the preretinal neovessels in OIR. As a cell and tissue-penetrating peptide, CAR also penetrated into the retina. Hyperoxia used to induce OIR in the retina also causes bronchopulmonary dysplasia in the lungs. We showed that the CAR peptide is not targeted to the lungs in normal mice but is targeted to the lungs after hyperoxia-/hypoxia-treatment of the animals. The site-specific delivery of the CAR peptide to the pathologic retinal vasculature and the penetration of the retinal tissue may offer new opportunities for treating retinopathies more selectively and with less side effects.