Therapeutic advances in vascular disease may have far-reaching public benefits. Bone morphogenetic proteins (BMPs) are emerging as essential regulators of the vasculature, important in disorders such as arteriovenous malformations (AVMs). Previous studies have shown that BMP-4 and Matrix Gla Protein (MGP), a BMP antagonist, regulate the expression of the activin-like kinase receptor 1 (ALK1), essential in angiogenesis. Stimulation of ALK1 by its ligand BMP-9 then regulates endothelial proliferation and maturation. Our preliminary data show that ALK1 signaling is instrumental in regulating Notch signaling, which has been associated with cerebral AVMs. The data further show that MGP deficiency enhances both BMP and Notch signaling resulting in the formation of cerebral AVMs and abnormal differentiation of vascular endothelial cells (ECs). MGP deficiency also causes the expression of stem cell markers in endothelial cells and disrupts normal lumen formation. Together, the results suggest that MGP plays a critical role in the crosstalk between BMP and Notch signaling during vascular development. We hypothesize that MGP helps maintain the balance between BMP and Notch signaling, which directs normal vascularization, and that elevated BMP signaling enhances Notch signaling and leads to AVMs. We further hypothesize that a limitation of Notch signaling would reduce cerebral AVMs in MGP deficiency, in part by limiting stem cell characteristics in vascular cells and abnormal lumen formation.
Specific Aim 1 will test the effects of MGP on the interactions between BMP signaling and Notch signaling during EC differentiation in vitro and in vivo.
Specific Aim 2 will determine if a reducton in Notch signaling compensates for MGP deficiency and limits cerebral AVMs by breeding the MGP deficient mice with mice deficient in Notch ligands Jag1 or Jag2. We predict that lower levels of Notch ligands will limit the cerebral AVMs due to MGP deficiency.
Specific Aim 3 will determine the role of MGP in regulating endothelial stem cell characteristics and vascular lumen formation as part of the formation of AVMs using MGP depletion in vitro and lineage tracing in vivo. If successful, the obtained information may translate into strategies for using BMP and Notch inhibitors in the treatment of cerebral AVMs.
Our studies are relevant to the diagnosis and treatment of diseased vessels in the brain, including co-called arteriovenous malformation and hereditary hemorrhagic telangiectasia, a genetic disorder. This study focuses on factors referred to as bone morphogenetic proteins and Notch, and how they communicate with each other to regulate the formation of the vessel lining and the vessel lumen. Understanding how these factors work may lead to new strategies for prevention and treatment.
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