Blood vessels in development and disease
The overall research in the Stuhlmann lab focuses on understanding the molecular and genetic pathways that regulate the three principal processes of vascular development: endothelial cell lineage determination, vasculogenesis, and angiogenesis. In a genetic screen for early developmental genes in mouse embryonic stem cells (ESC) and embryos, we have identified an endothelial-specific gene, Egfl7. Interestingly a microRNA, mir-126, is embedded in an intron of the endogenous Egfl7 gene and is co-regulated with Egfl7. Egfl7 encodes a secreted, “angiocrine” factor that is expressed in endothelial progenitors, and in actively proliferating blood vessels during developmental and pathological angiogenesis. Egfl7 loss-of-function and overexpression studies, and miR-126 loss-of-function studies demonstrated that both play important roles during the development and maintenance of the vascular system, and in pathologies of blood vessels.
Presently, research in the Stuhlmann lab focuses on two major areas:
- Role of Egfl7 in endothelial progenitor cells and during specification of the endothelial lineage.
We have generated a “reporter mouse” model in which a fluorescent GFP marker is expressed under Egfl7 transcriptional control. We are using the model to dissect the pathways that direct specification of the endothelial cell lineage, including formation of the progenitors of the hematopoietic lineage and hematopoietic stem cells.
- Role of Egfl7 and miR-126 in placentation and placental disease.
The development of a functional placenta is crucial for the growth and survival of the mammalian embryo. The fetal and maternal vasculature in the placenta facilitates an intricate interface for the exchange of nutrients, gases, hormones and immune cells. We recently discovered that mice with loss-of-function mutations specific for Egfl7, or for miR-126, display distinct placental defects. Furthermore, EGFL7 protein is detected in the serum women during pregnancy and EGFL7 levels are dysregulated in serum of women with complicated pregnancies. For our ongoing studies we are complementing in vitro approaches including trophoblast stem cells and endothelial cells, with mouse models and, human tissue and serum samples. We anticipate that the mutant mice will serve as models to better understand human pregnancy-associated diseases, including preeclampsia and diabetes.