New role for versatile BMP interpretation: regulation of endothelial cell heterogeneity in the mouse

Defects in the formation of blood and lymphatic vessels contribute to the pathogenesis of malignant, inflammatory, and chronic disorders. Endothelial cells (EC) form the inner lining of vessels. Genetic evidence linking impaired bone morphogenetic protein (BMP) signaling to vascular development in the embryo and disease in the adult is strong, but unaddressed for involvement in lymphatic development and disease.

Three teams join forces to study BMPSmad mediated signaling in vascular development using in vivo mouse models and gain and loss-of-function in cell cultures. AZ/LU and AL have demonstrated a role for Smad proteins and Msx transcription factors (target genes of BMP signaling) in regulating heterogeneity of angiogenic and arterial versus venous endothelium respectively, indicative of BMP signaling affecting vessel plasticity, patterning and remodeling.

In this project, studies will be extended towards other types of endothelium, including also lymphatic endothelium. Lately, DH has shown that the Smad-interacting transcription factor Sip1 functions as a hub integrating fastforward and negative feed-back in myelination and hematopoiesis, and acts as both a repressor and an activator of transcription. Such a dual role of Sip1 in Smad- and/or Msxmediated BMP signaling events in endothelium will be investigated. An understanding of the unique structural and functional properties of each vascular bed holds important clues to sitespecific diagnostics and therapeutics.