Regulation of BMP-dependent angiogenesis via SMAD7 and PMEPA1 inhibitory proteins (2016)

Undergraduates: Kathryn Citrin, Lyndsay Wylie Kevin Mouillesseaux, Victoria Bautch

Faculty Advisor: Victoria Bautch
Department: Biology

---

Angiogenesis, the development of blood vessels from existing vasculature via sprouting of endothelial cells, is regulated by growth factor signaling. One such signal is BMP, a TGFb superfamily member. BMP ligand binding to its receptor phosphorylates SMAD1/5/8 intracellular proteins for nuclear translocation and transcription regulation.1 Another signal called Notch downregulates endothelial cell responsiveness to BMP signaling by mechanisms that are not fully understood. A screen to identify Notch-regulated BMP/TGFb pathway members identified two proteins upregulated by Notch that negatively regulate BMP signaling, PMEPA1 and SMAD7.1,2 Understanding the function of these Notch-regulated BMP/TGFb pathway inhibitors is critical, as they hold therapeutic potential for diseases of aberrant BMP signaling.3 Knockdown of PMEPA1 expression significantly increased nuclear fluorescence of phosphorylated SMAD1/5, which is a readout of upregulated BMP signaling. However, SMAD7 knockdown did not affect BMP responsiveness. These data indicate that PMEPA1 inhibits BMP signaling in endothelial cells, a novel finding that warrants further investigation. Experiments designed to test the effect of reduced levels of PMEPA1 or SMAD7 in a 3D blood vessel formation sprouting assay are currently underway. We hypothesize that PMEPA1 is an important protein that allows endothelial cells to set their responsiveness to BMP by virtue of their Notch status.