Implications of epigenetic mechanisms for vascular development and disease.

to the blind-ending lymphatic vasculature, the blood vasculature represents a closed circulating system and facilitates the exchange of gases (i.e., O 2 and CO 2 ) and nutrients [1]. Although both BECs and LECs display distinct features and functions, they share a close molecular and developmental relationship. In the early embryo, progenitor cells, the so-called angioblasts, differentiate from the mesodermal compartment and establish a primitive vascular network [2,3]. After determination of arteries and veins, venous endothelial cells further transdifferentiate into LECs forming primary lymph sacs [1]. This process is carefully regulated and requires a defined expression of lineage-specifying genes (i.e., PROX1) [4]. After terminal endothelial differentiation both LECs and BECs are characterized by distinct gene-expression profiles regulating cell type-specific functions [5]. There is growing evidence to suggest that epigenetic mechanisms (i.e., DNA methylation at CpG dinucleotides and histone modifications) are involved in regulating vascular endothelial gene-expression changes during development and in maintaining cell-type-specific expression patterns in adulthood. For example, histone deacetylase activity has been implicated in the regulation of embryonic endothelial differentiation [6], and histone acetylation controls the expression of NOTCH4 [7], a key signaling molecule involved in vascular development and remodeling. Furthermore, shear stress, which is a particularly distinctive stimulus for vessels and vessel-associated diseases, can alter chromatin structure and change the gene-expression profile in cultured human endothelial cells [8]. In addition, histone modifications such as H3K4 methylation are involved in vessel sprouting and endothelial cell migration [9]. However, the role of Nearly all cells of the human body have an identical genetic background. Nevertheless, cellular specialization into distinct functional entities is a hallmark of biological complexity in multi cellular organisms. But how can a single stem cell give rise to a variety of functionally different cell types? During past decades it has become clear that epigenetic mechanisms play a crucial role in regulating cell type-specific gene expression and thereby contribute to the determination of cellular fate. Furthermore, alterations of epigenetic signatures cause a variety of diseases. The fact that epigenetic marks are reversible makes them an attractive target for therapeutic interventions, aiming at reconstituting a healthy phenotype by reversing aberrant methylation marks. The present editorial summarizes the latest findings on epigenetic regulation and disease-associated dysregulation of blood and lymphatic vessel formation, focusing primarily on the characterization of blood endothelial cells (BECs) and lymphatic endothelial cells (LECs). Although both cell types share a close developmental relationship, they show specific functional differences. Thus, BECs and LECs represent an interesting model system to investigate the involvement of epigenetic mechanisms in regulating these cell-type-specific functions. We will further discuss whether treatment approaches targeting aberrant methylation marks may represent a rewarding strategy to recover epigenetically induced functional disorders of the vascular systems. The human vasculature is characterized by two types of tubular networks; the blood and the lymphatic systems, which comprise different but interdependent functions. The lymphatic system regulates tissue fluid homeostasis, immune surveillance, and absorption of fluids and macromolecules from the interstitium [1]. In contrast