Osteoglycin’s embracement of VEGF receptor-2 limits angiogenesis and collateralization

The circulatory system regulates adequate distribution of blood and delivery of oxygen and nutrients to the tissues. When arterial blood flow is interrupted a rapid neovascularization response occurs by expansion of collateral blood vessels and angiogenic sprouting in the hypoxic tissue. VEGF-A plays a central role in hypoxia-induced angiogenesis. According to insight obtained from developing tissues, VEGF-A binds to VEGF receptor-2 dimers on the protruding filopodia of sprouting endothelial tips. The receptor is subsequently internalized, after which intracellular signalling evokes a proper sprouting response. However, clinical studies in which VEGF was used to induce angiogenesis in chronically ischemic heart or limb have been unsuccessful. Apparently these tissues are refractory to VEGF stimulation. It is generally assumed that the extracellular matrix harbours information that regulates and guides endothelial sprouting. Matrix association of VEGF-A via its heparin-binding domain can direct the invading sprout, while angiogenesis inhibitors such as thrombospondin and matrikines (proteolytically generated matrix fragments that modulate angiogenesis) do the opposite. In this issue of Cardiovascular Research, Wu et al. report on a potentially important role of osteoglycin in limiting the cellular response to VEGF. Osteoglycin inhibits the VEGF-VEGFR2 interaction in healthy tissue, while its absence in the ischemic mouse hindleg enhances both sprouting angiogenesis and collateralization. Osteoglycin (gene symbol: OGN), also called mimecan (UniProt entry name: MIME), is a member of the small leucine-rich proteoglycans (SLRPs) and is expressed in most cells of the body. Many SLRPs including osteoglycin can bind to matrix proteins, can expose a binding site to collagen fibrils, and can act as a paracrine factor that modulates cell signalling, e.g. by interacting with specific tyrosine kinase receptors. Like other SLRPs, osteoglycin is secreted and acts extracellularly. While there is one OGN gene, which is translated into one precursor protein of 298 amino acids, the protein undergoes posttranslational modification by glycosylation, in particular keratan sulfation, and proteolytic cleavage resulting in various products ranging from 12 to 50 kD. The spectrum of actions is further extended by the fact that differentially spliced OGN mRNAs are transcribed, which not only are translated into the precursor protein, but also may interact directly with other RNAs or proteins. Osteoglycin has been connected to many types of disease through changes in its gene expression and antigen and/or circulating protein levels. Such pathologies include various types of cardiovascular and neurological disease, eye and bone disease and cancer (recently summarized by Deckx et al.) Lung and adipose tissue also express osteoglycin, which can be released into the circulation. Indeed, circulating osteoglycin has been reported to act on the regulation of food intake by inducing hypothalamic cytokines. In various healthy and cancer cells, elevated osteoglycin expression was paralleled by a reduced proliferation, while osteoglycin deletion enhanced proliferation. Interest in the role of osteoglycin in cardiovascular disease was initiated by an integrated genomic analysis that identified osteoglycin as a major candidate regulator of left ventricular mass in the rat. This conclusion was further supported by a small genomic study in man that confirmed such role for osteoglycin and by in vitro experiments showing decreased OGN transcription in phenylephrine-induced cardiomyocyte hypertrophy. In mouse myocardial infarction tissue, osteoglycin deletion increased rupturerelated mortality, while increased expression of osteoglycin was associated with proper collagen maturation and deposition. In this way, osteoglycin protects against cardiac rupture and limits adverse remodelling after myocardial infarction. Additional studies in man showed an association between osteoglycin expression and collagen deposition in human myocardial infarction tissue. Furthermore, circulating osteoglycin has been suggested as a biomarker for heart failure. Additional studies implied differential expression of osteoglycin in atherosclerotic vessels, but another study debated a functional role of this factor in atherosclerosis. Osteoglycin mRNA was negatively related to the extent of aortic hypertrophy in rats, while osteoglycin deletion caused an increase in angiotensin II stimulated proliferation of cultured smooth muscle. Interestingly, osteoglycin was also identified as a differentially expressed gene that was downregulated in collateral arteries after rabbit femoral artery ligation. A role in collateralization was further suggested by a recent study in 559 consecutive patients with stable angina and