Stochastic phenotypic switching in endothelial cell heterogeneity

Abstract Ubiquitous biological noise—random variation in the rate of molecular processes—is known to result in variable gene expression among isogenic cells. Such heterogeneity can synergize with phenotypic plasticity of the regulatory system to generate functionally distinct, dynamic phenotype-mosaics. Here we discuss parallels between phenotypic plasticity in response to environmental versus noise-driven variation. In a case study of in vivo mosaic heterogeneity, we detail evidence that in mice the endothelial von Willebrand factor (vWF) gene is expressed in a mosaic ON/OFF pattern in several capillary beds. This vWF mosaicism is dynamic; clonal analysis of cultured endothelial cells indicates that it is generated by random transitions of a noise-sensitive bistable switch. Finally, the hearts of vWF-null mice show abnormal capillary structure and cardiac dysfunction. Our findings suggest that stochastic phenotype switching may be a homeostatic strategy in the adult vasculature, and more generally, a requirement of healthy tissue function.