Study of the role of activin receptor like kinase-1 signaling in control of vascular endothelial growth factor expression and atherosclerosis

The Transforming Growth Factor-beta (TGFbeta) superfamily of proteins is associated with the pathogenesis of many vascular diseases. Activin receptor like kinase-1 (ALK1) is a serine/threonine type I receptor that belongs to the TGFbeta superfamily of proteins and plays a critical role in angiogenesis. The homozygous ALK1 deficient mouse is embryonic lethal by E9.5 from severe vascular abnormalities. Mutations of ALK1 are also a cause of the human disease Hereditary Hemorrhagic Telangiectasia, which is characterized by the progressive development of arteriovenous malformations systemically. At the time the work for this dissertation began, ALK1 was considered a TGFbeta receptor because some studies showed it to be activated by the TGFbeta ligands 1 and 3 through the TGFbeta receptor type II (TbetaRII). However, others considered ALKI an orphan receptor because they were unable to reproduce these findings and found that ALKI bound to other ligands and receptors, though these complexes did not generate any signaling activity.Because mutations of ALK1 are associated with pulmonary arterial hypertension, which is also associated with mutations of BMP receptor type II (BMPRII), another member of the TGFbeta superfamily, we hypothesized that ALK1 uses BMPRII to signal. Because VEGF expression is induced by both TGFbeta1 and transfection of constitutively active ALKI, we further hypothesized that ALK1 is the receptor responsible for mediating this effect. Finally, we hypothesized that ALK1 deficiency is atheroprotective because when this work was begun TGFbeta1, an atheroprotective cytokine, was the only ligand that had been shown to activate ALK1 activity.The results of Chapter 2 demonstrated that ALK1 uses BMPRII and the ligand, bone morphogenetic protein-9 (BMP-9) to signal. This complex can function independently of TGFbeta, ALK5, and TbetaRII. Our data further shows that ALK1 does not use TGFbeta or TbetaRII to signal, suggesting that ALKI should be re-classifed as a BMP receptor. In Chapter 3 we showed that the BMP-9/ALKI/BMPRII complex inhibits the induction of vascular endothelial growth factor (VEGF) by TGFbeta1. The induction of VEGF by TGFbeta is mediated by ALK5 and TbetaRII, suggesting that ALK1 and ALK5 may act as ON/OFF switches during angiogenesis, respectively. Finally, in Chapter 4 our experiments showed that ALKI deficiency does not have an effect on atherosclerosis in male mice.Chapter 5 discusses the results of this dissertation and presents a working model that explains how ALK1 might interact with ALK5 during vascular development and remodeling and how perturbations in ALK1 signaling might lead to disease. Lastly, we suggest that ALK1 signaling deficiency may be a molecular mechanism and potential therapeutic target common to three very distinct diseases which are all characterized by the post-gestational development of arteriovenous malformations.