Dokument

Summary:
Bone Morphogenetic Proteins (BMPs) are members of the well known Transforming Growth Factor (TGF) superfamily, consisting of TGF β proteins, Activins and Growth Differentiation Factors (GDFs). These factors play an essential role in numerous different aspects of embryonic development and physiological organ function. BMP9 and BMP10 are members of this superfamily; however their role, especially in the cardiovascular system, is still poorly characterised. BMP9 is produced by and is secreted from the liver and is proposed to act as a major circulating vascular quiescence factor. BMP10, however, has a more limited expression where it is expressed during embryonic development in the ventricles from embryonic day (E) 9.0 to 13.5. After E 14.5, expression of BMP10 declines in the ventricles, but is maintained in the right atria of postnatal and adult hearts. BMP9 and BMP10 bind with high affinity to ALK1, an endothelial specific receptor as well as to endoglin (ENG), a TGF β co-receptor. Since both of these ligands bind with very high affinity to the ALK1 receptor and soluble ENG receptor, it was suggested that BMP9 and BMP10 are important mediators of cardiovascular development and homeostasis. So far it has been shown that mutations in ALK1, ENG and SMAD4 genes can result in hereditary haemorrhagic telangiectasias (HHT), which is a disease that results in vascular abnormalities. BMP10 along with ENG has been shown to be involved in pre-eclampsia, a disease resulting in high blood pressure (BP), thus strengthening the argument that these BMP family members are involved in cardio vascular homeostasis. The aim of this project was to elucidate the role of BMP9 and BMP10 in the adult heart and the ir role in cardiovascular homeostasis. Constitutive BMP9 knockout mice were generated, with a conditional heart-specific BMP10 deletion under the control of ANF Cre. Results demonstrated that the loss of BMP9 and BMP10 leads to vessel defects which caused disruption in vascular tone and altered cardiac function. In summary, these results have identified an essential role for BMP9 and BMP10 in postnatal cardiac remodelling and vascular homeostasis.

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