Abstract
Angiogenesis is the formation of new vessels from pre-existing vasculature. The heparan sulfate chains from endothelial cell proteoglycans interact with the major angiogenic factors, regulating blood vessels´ formation. Since the FDA´s first approval, anti-angiogenic therapy has shown tumor progression inhibition and increased patient survival. Previous work in our group has selected an HS-binding peptide using a phage display system. Therefore, we investigated the effect of the selected peptide in angiogenesis and tumor progression. The HS-binding peptide showed a higher affinity for heparin N-sulfated. The HS-binding peptide was able to inhibit the proliferation of human endothelial umbilical cord cells (HUVEC) by modulation of FGF-2. It was verified a significant decrease in the tube formation of human endothelial cells and capillary formation of mice aorta treated with HS-binding peptide. HS-binding peptide also inhibited the formation of sub-intestinal blood vessels in zebrafish embryos. Additionally, in zebrafish embryos, the tumor size decreased after treatment with HS-binding peptide.
Highlights
Angiogenesis is forming new vessels from pre-existing vasculature during embryonic development and adult life [1].Among the angiogenic factors that participate in neovascularization, we highlight the vascular endothelial growth factor (VEGF), hypoxia-induced factor (HIF), placental growth factor (PGF), The Heparan Sulfate Binding Peptide fibroblast growth factor (FGF), angiopoietin-1 (Angp), plateletderived growth factor (PDGF), tumor necrosis factor (TNF), interleukins (IL), epidermal growth factor (EGF), insulin-like growth factor (IGF), angiogenin (Ang), stromal cell-derived factor (SDF) and transforming growth factor (TGF) [2].The heparan sulfate (HS) chains from endothelial cell proteoglycans interact with the major angiogenic factors, regulating blood vesselsformation [3]
The results showed that the scrambled peptide has lower specificity since it binds with other glycosaminoglycans and presents a higher affinity to heparin than the HS-binding peptide
The assay using such peptide was performed with transgenic zebrafish embryos Tg (Fli1:eGFP), that express a green fluorescent protein (GFP) in blood vessels, which allowed us to investigate some effect of the HS-binding peptide in vivo
Summary
The heparan sulfate (HS) chains from endothelial cell proteoglycans interact with the major angiogenic factors, regulating blood vesselsformation [3]. HS can modulate the release of such angiogenic factors after the action of the enzyme heparanase or proteoglycan cleavage by proteases, forming a concentration gradient that may direct angiogenesis [5,6,7]. Heparin and HS exhibit structural similarities and share the same biosynthetic pathway. Both HS and heparin are formed by repeated disaccharide units of glucosamine and uronic acid (D-glucuronic acid or L-iduronic acid) residues linked by glycosidic a-intradisaccharide and b-interdisaccharide bonds [5, 7, 8]
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