SMAD6 FUNCTION IN DEVELOPING MURINE BLOOD VESSELS AND ENDOTHELIAL CELL JUNCTIONS

Endothelial cells line the inside of blood vessels and are activated by angiogenic cues to promote the formation of new blood vessel sprouts, a process called sprouting angiogenesis. For sprouting to be initiated, endothelial cells first modulate their adherens junctions to allow for cell rearrangements. The Bone Morphogenetic Protein (BMP) pathway is a potent regulator of angiogenesis. SMAD6, a major intracellular inhibitor of BMP signaling, is required for homeostasis of the cardiovascular system in the adult. Here, we examine the function of SMAD6 during mouse embryonic development, and find that global loss of Smad6 results in embryonic vessel hemorrhage and is lethal by postnatal day (P)0 with moderate penetrance. SMAD6 is expressed developmentally in the heart and in a subset of arteries. We show that loss of Smad6 also leads to angiogenic defects in the postnatal retina, as Smad6-/- retinas show increased sprouting at the vascular front and in the retina plexus. Closer examination revealed disorganized localization of the major adherens junction protein in endothelial cells, VE-cadherin, in Smad6-/- retinas. In vitro, knockdown of SMAD6 results in increased VE-cadherin area and increased VE-cadherin internalization, suggesting activated endothelial cells with decreased barrier function. Thus, we highlight novel roles for SMAD6 in the stabilization of endothelial cell junctions and angiogenesis that can be used to advise blood vessel therapies.Doctor of Philosoph