Arteries and veins are molecularly distinct even before blood begins to flow, but the mechanisms that facilitate these molecular distinctions are incompletely defined. We have recently identified a novel role for the SWI/SNF chromatin-remodeling complex in mediating venous specification (Davis et al, 2013). The SWI/SNF ATPase BRG1 helps promote expression of the transcription factor COUP-TFII in developing veins. In the absence of BRG1, venous endothelial cells downregulate Coup-TFII and aberrantly express arterial markers. This work is significant because it provides the first description of a factor promoting Coup-TFII expression in vascular endothelium and defines a new role for chromatin remodeling in venous specification. We are currently expanding upon this work by questioning how BRG1 facilitates Coup-TFII expression in veins while preventing its expression in arteries. We are also exploring novel roles for the NuRD chromatin-remodeling complex in vascular specification.
The lymphatic circulatory system is a network of vessels that is distinct from blood vessels but that originates from veins during embryonic development. We observe striking lymphatic phenotypes when we delete chromatin-remodeling enzymes from vascular endothelium, including severe embryonic edema and blood-filled lymphatic vessels. In the case of Chd4 mutants, we found that these phenotypes arise because of aberrant plasmin-mediated degradation of blood clots at the interface between the blood and lymphatic systems (Crosswhite et al, 2016).
We are identifying novel roles for chromatin-remodeling complexes in regulating vascular integrity. Embryos depleted of the chromatin-remodeling enzyme CHD4 in developing blood vessels undergo sudden vascular rupture and lethal hemorrhage at midgestation. We have discovered that CHD4 regulates extracellular matrix proteolysis by preventing excessive activation of the protease plasmin. Loss of CHD4 results in elevated plasmin activation, matrix breakdown and vascular fragility at multiple stages of embryonic development (Ingram et al, 2013; Crosswhite et al, 2016). We are extending our studies to determine whether CHD4 likewise suppresses plasmin activation and promotes vascular integrity in adult mice.
Necroptosis (programmed necrosis) is a newly identified form of cell death with unknown causes and effects in the vasculature. We are studying various mechanisms for transcriptionally regulating endothelial cell necroptosis and are considering the impact of this death modality on embryonic and postnatal vasculature. Our genetic and cellular approaches toward studying necroptosis are revealing exciting new paradigms about endothelial cell survival cues that maintain vascular integrity.
Although many of our research focus areas have emerged from embryonic vascular phenotypes we have observed, we are keenly interested in defining roles for chromatin-remodeling complexes in postnatal vascular development. Therefore we are deleting chromatin-remodeling enzymes from postnatal vasculature and assessing vascular phenotypes in tumor models, exercised muscles, and the neonatal retina. So far we have learned that the SWI/SNF chromatin-remodeling complex is surprisingly dispensable in multiple models of postnatal angiogenesis (Wiley et al, 2015). This speaks to the temporal specificity that chromatin-remodeling complexes utilize when regulating their target genes and may indicate functionally redundant roles for SWI/SNF and other chromatin-remodeling complexes during physiological and pathological postnatal vascular growth.