The Wilms' tumor suppressorWt1is expressed in the coronary vasculature after myocardial infarction

Abstract

Expression of the Wilms' tumor gene Wt1 in the epicardium is critical for normal heart development. Mouse embryos with inactivated Wt1 gene have extremely thin ventricles, which can result in heart failure and death. Here, we demonstrate that Wt1 can be activated in adult hearts by local ischemia. Wt1 mRNA was increased more than twofold in the left ventricular myocardium of rats between 1 day and 9 wk after infarction. Wt1 expression was localized by means of mRNA in situ hybridization and immunohistochemistry to vascular endothelial and vascular smooth muscle cells in the border zone of the infarcted tissue. A strikingly similar distribution was seen for vascular endothelial growth factor and two different cell proliferation markers in the coronary vessels of the ischemic heart. No Wt1 could be detected in the vasculature of the noninfarcted right ventricles. Wt1 expression in the coronary vessels of the ischemic heart was mimicked by exposure of rats to normobaric hypoxia (8% O2) and 0.1% CO, respectively. These findings demonstrate that Wt1 is expressed in the vasculature of the heart in response to local ischemia and hypoxia. They suggest that Wt1 has a role in the growth of coronary vessels after myocardial infarction.

The Wilms' tumour suppressor WT1 is involved in endothelial cell proliferation and migration: expression in tumour vessels in vivo

“…This extends a recent study, which described WT1 expression in WT1 activates ETS-1 in endothelial cells N Wagner et al angiogenic tumours of the skin (Timar et al, 2005). The partial co-localization of WT1 with proliferation markers in tumour vessels and the diminished proliferation, migration and tube formation of endothelial cells in vitro upon silencing of WT1 is in agreement with our recent observations that WT1 is required for coronary vessel formation during embryonic development (Wagner et al, 2005) and it is expressed in microvessels after myocardial infarction, but not in vessels of adult control hearts (Wagner et al, 2002). These data suggest that WT1 is involved actively in proliferation of endothelial cells and vessel formation rather than being only a novel endothelial cell marker.…”

“…Immunohistochemical double labelling of tumour samples revealed an overlapping expression of both proteins tumour endothelia ( Figures 6C and D). As reported earlier, WT1 showed some additional expression in vascular smooth muscle cells (Wagner et al, 2002). To investigate whether WT1 might be able to directly transcriptionally activate ETS-1, we cloned the published mouse ETS-1 promoter (Jorcyk et al, 1997) into a luciferase reporter vector and performed transient co-transfection experiments with expression plasmids encoding the WT1(ÀKTS) or WT1( þ KTS) splice variants as described by Wagner et al (2005).…”

The epicardium and epicardially derived cells (EPDCs) as cardiac stem cells

“…The majority of the cells within the subepicardium express RALDH2 as well as WT1, whereas the EPDCs that migrate into the myocardium gradually loose their RALDH2 expression while retaining the expression of WT1. It is likely that this persistence of WT1 expression is related to the maintenance of the undifferentiated stem cell state in these EPDCs (Carmona et al, 2001;Pérez-Pomares et al, 2002b;Wagner et al, 2002), a mechanism also suggested for hematopoietic progenitors (Baird and Simmons, 1997).…”

The Wilms’ tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression

“…6d-f). Cell types, which normally express Wt1, that is, podocytes of the kidney and epicardial cells of the heart 17,28,29 showed no histological differences upon Tie2-Cre-mediated knockout of Wt1 ( Supplementary Fig. 6g,k), suggesting specificity of Tie2-Cre.…”