Loss-of-function mutations in the activin-like kinase 1 receptor gene (ALK1) cause Osler Rendu Weber (ORW), an autosomal dominant vascular dysplasia characterized by arteriovenous malformations. ALK1 encodes an orphan endothelial receptor that exhibits homology to receptors for the TGF-beta superfamily of growth factors. To define the role of Alk1 in vascular development and disease, the investigators have generated mice lacking Alk1 (Alk1 -/-). First, the investigators will determine the role of Alk1 in vessel identity. Preliminary data indicate that Alk1 -/- mice suffer from arterial-venous shunting and defective angiogenesis. We postulate that Alk1 is required for endothelial cells to differentiate into arterial and venous fates. We will characterize Alk1 -/- mice using histology, immunohistochemistry, in situ hybridization, and electron microscopy. The investigators expect the failure in endothelial differentiation and vessel identity will cause defective vascular remodeling and arterial smooth muscle cell development. These studies will determine whether Alk1 is required for arteries and veins to develop into distinct vascular networks. Second, because ORW is caused by functional hemizygosity of ALK1, we will study the pathogenesis of ORW by examining Alk1 +/- mice. Our preliminary data indicate that similar to humans with ORW, Alk1 +/- mice have a shortened life expectancy and abnormal capillary organization. We predict that Alk1 +/- mice will model ORW and enable us to study the development of vascular dysplasia within the brain, liver, lung, and gastrointestinal tract. These experiments will determine whether the pathogenic mechanism responsible for ORW is failed angiogenesis during organogenesis. Third, the investigator will identify endothelial factors that induce vascular smooth muscle (VSMC) differentiation. Because VSMCs fail to differentiate in Alk1 -/- embryos, the investigators postulate that Alk1 regulates the synthesis of endothelial factors that are essential for VSMC differentiation. The investigators have isolated endothelial cells from Alk1 +/+ and Alk1 -/- embryos, and are identifying differentially expressed genes. In contrast to Alk1 +/+ cells, the investigators predict Alk1 -/- endothelial cells will be incapable of inducing multipotential mesenchymal cells (10T1/2) to differentiate into vascular smooth muscle cells. The investigators will identify which differentially expressed genes are responsible for cellular differences observed in Alk1 +/+ and Alk1 -/- endothelial cells. In summary, this grant proposal aims to demonstrate that Alk1 is required for vessel identity and that vessel identity is important for angiogenesis and human vascular disease.
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