The transcriptomic and epigenetic map of vascular quiescence in the continuous lung endothelium.

Maintenance of a quiescent and organotypically-differentiated layer of blood vessel-lining endothelial cells (EC) is vital for human health. Yet, the molecular mechanisms of vascular quiescence remain largely elusive. Here we identify the genome-wide transcriptomic program controlling the acquisition of quiescence by comparing lung EC of infant and adult mice, revealing a prominent regulation of TGFß family members. These transcriptomic changes are distinctly accompanied by epigenetic modifications, measured at single CpG resolution. Gain of DNA methylation affects developmental pathways, including NOTCH signaling. Conversely, loss of DNA methylation preferentially occurs in intragenic clusters affecting intronic enhancer regions of genes involved in TGFß family signaling. Functional experiments prototypically validated the strongly epigenetically regulated inhibitors of TGFß family signaling SMAD6 and SMAD7 as regulators of EC quiescence. These data establish the transcriptional and epigenetic landscape of vascular quiescence that will serve as a foundation for further mechanistic studies of vascular homeostasis and disease-associated activation.

Microvascular Mural Cell Organotypic Heterogeneity and Functional Plasticity.

Microvascular mural cells (MMCs), comprising pericytes and microvascular smooth muscle cells, are of increasing interest in multiple fields of research for their plasticity and their organotypic functional roles in microvascular homeostasis and disease. They have been described as a heterogeneous cell population constituting a continuum of cell phenotypes along the microvascular bed with vascular smooth muscle cells (VSMCs) at one end of the spectrum and pericytes at the other end. MMC organotypic subpopulations have been suggested to function in a tissue-context-dependent manner, thereby contributing to organ-specific functional roles. However, the phenotypic and organotypic heterogeneity as well as their origin and marker identification are hitherto poorly defined. Here we review recent work and emerging concepts regarding MMC phenotypic and organotypic heterogeneity and their functional plasticity in health and disease.