Functional Overlap Between Chondroitin and Heparan Sulfate Proteoglycans During VEGF-Induced Sprouting Angiogenesis

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 32; no. 5; pp. 1255 - 1263
• Main Authors: Jan, Sébastien Le, Hayashi, Makoto, Kasza, Zsolt, Eriksson, Inger, Bishop, Joseph R, Weibrecht, Irene, Heldin, Johan, Holmborn, Katarina, Jakobsson, Lars, Söderberg, Ola, Spillmann, Dorothe, Esko, Jeffrey D, Claesson-Welsh, Lena, Kjellén, Lena, Kreuger, Johan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.05.2012; Lippincott Williams & Wilkins
• Subjects: Angiogenesis; Animals; Atherosclerosis (general aspects, experimental research); Biologi med inriktning mot molekylärbiologi; Biological and medical sciences; Biology with specialization in Molecular Biology; Blood and lymphatic vessels; Blotting, Western; Cardiology. Vascular system; Cell Adhesion - drug effects; Cell Proliferation; Cells, Cultured; Chondroitin; chondroitin sulfate; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug toxicity and drugs side effects treatment; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; ext1; heparan sulfate; Heparan Sulfate Proteoglycans - metabolism; Immunohistochemistry; Medical sciences; Medicin; Medicin och hälsovetenskap; Medicine; Mice; Neovascularization, Pathologic - chemically induced; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Pharmacology. Drug treatments; proteoglycan; Proteoglycans - metabolism; Signal Transduction - drug effects; Toxicity: blood; Vascular Endothelial Growth Factor A - pharmacology; Vascular disease; Proteoglycan; Angiogenesis; developmental; biology; Atherosclerosis; Cardiovascular disease; Chondroitin sulfate; vascular biology; glycosominoglycan; Endothelium
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.111.240622

OBJECTIVE—Heparan sulfate proteoglycans regulate key steps of blood vessel formation. The present study was undertaken to investigate if there is a functional overlap between heparan sulfate proteoglycans and chondroitin sulfate proteoglycans during sprouting angiogenesis. METHODS AND RESULTS—Using cultures of genetically engineered mouse embryonic stem cells, we show that angiogenic sprouting occurs also in the absence of heparan sulfate biosynthesis. Cells unable to produce heparan sulfate instead increase their production of chondroitin sulfate that binds key angiogenic growth factors such as vascular endothelial growth factor A, transforming growth factor β, and platelet-derived growth factor B. Lack of heparan sulfate proteoglycan production however leads to increased pericyte numbers and reduced adhesion of pericytes to nascent sprouts, likely due to dysregulation of transforming growth factor β and platelet-derived growth factor B signal transduction. CONCLUSION—The present study provides direct evidence for a previously undefined functional overlap between chondroitin sulfate proteoglycans and heparan sulfate proteoglycans during sprouting angiogenesis. Our findings provide information relevant for potential future drug design efforts that involve targeting of proteoglycans in the vasculature.