Epigenetic Control of Angiogenesis via DNA Methylation

Abstract

Why some patients develop limb- and life-saving collaterals but others do not constitutes one of the great challenges that face patients with peripheral vascular and coronary artery disease. A longstanding goal in vascular disease is the establishment of therapies that enhance angiogenesis in compromised tissue beds. To achieve this goal, however, it is essential to define and understand the underlying mechanisms that control angiogenesis and may distinguish individual patient capacity for collateral formation. In this issue of Circulation , Rao and colleagues1 report that ischemic injury increases DNA methylation in several genes critical for angiogenesis. The methyl-CpG–binding domain 2 (MBD2) protein senses DNA methylation and mediates transcriptional repression of genes involved in angiogenesis and endothelial cell survival. This seminal report mechanistically links epigenetic changes in vascular cells to angiogenesis, paving the way for new therapies that could improve perfusion in patients with vascular disease. Article see p 2964 In mammals, cytosine methylation (5-methylcytosine) is a common epigenetic modification, occurring primarily in regions of DNA where a cytosine nucleotide is adjacent to a guanine nucleotide (so-called CpG sites). Up to 5% of cytosines are methylated, and nearly 60% of genes have CpG-rich islands in their 5′ regions.2 During embryonic development, DNA methylation dramatically declines by ≈30% in mice.3 Somatic cells and cancer cells also exhibit alterations in DNA methylation based on environmental stimuli. Because CG dinucleotides base pair to GC, methylation in 1 strand is mirrored by methylation in the other. During replication, methylation in the parent strand targets newly replicated DNA for methylation by recruiting DNA methyltransferases (DNMTs). In this way, stable transfer of gene methylation patterns to progeny lines is accomplished.4 DNA methylation is often present …