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Titel: Bone Morphogenetic Protein 9 and Bone Morphogenetic Protein 10 are Vital Factors in Maintaining Adult Vascular Homeostasis and Cardiac Function
Autor: Rice, Megan
Weitere Beteiligte: Braun, Thomas (Prof. Dr.)
Veröffentlicht: 2017
URI: https://archiv.ub.uni-marburg.de/diss/z2017/0517
DOI: https://doi.org/10.17192/z2017.0517
URN: urn:nbn:de:hebis:04-z2017-05176
DDC: 570 Biowissenschaften, Biologie
Titel(trans.): Knochenmorphogenetisches Protein 9 und Knochenmorphogenetisches Protein 10 sind wichtige Faktoren bei der Erhaltung der erwachsenen vaskulären Homöostase und Herzfunktion
Publikationsdatum: 2019-08-05
Lizenz: https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:

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.

Zusammenfassung:
Die knochenmorphogenetischen Proteine (engl.: bone morphogenic proteins, BMPs) sind Bestandteil der intensiv erforschten TGF-β Superfamilie (engl.: Transforming Growth Factor), hierzu zählen TGF-β Proteine, Activine, Wachstums- und Differenzierungsgene (engl.: Growth and differentiation factors, GDFs). Diese Proteine spielen eine essenzielle Rolle in zahlreichen Aspekten der Embryonalentwicklung und in physiologischen Organfunktionen. BMP9 und BMP10 sind Teil dieser Familie, deren Rolle im kardiovaskulären System weitgehend unbekannt. BMP9 wird in der Leber produziert und über das Blut im Organismus verteilt, wo es als zirkulierender Faktor an der vaskulären Ruhe beteiligt ist. Im Vergleich dazu ist die Expression von BMP10 strenger reguliert. Während der Embryonalentwicklung wird BMP10 ab Tag 9 (E9) in den Ventrikeln exprimiert. Ab E14.5 verlagert sich die Expression in die Atrien, wobei BMP10 im adulten Organismus nur noch im rechten Atrium exprimiert wird. BMP9 und BMP10 binden mit hoher Affinität an ALK1, einem endothelspezifischen Rezeptor, als auch an Endoglin (ENG), einem TGF-β-Korezeptor. Diese gemeinsamen Bindeeigenschaften sind ein Anzeichen dafür, dass BMP9 und BMP10 wichtige Mediatoren der kardiovaskulären Entwicklung als auch der vaskulären Homöostase sind. Bisher konnte gezeigt werden, dass Mutationen in den Genen für ALK1, ENG bzw. Smad4 verantwortlich für die Entstehung der sogenannten hereditären hämorrhagischen Teleangiektasie (HHT) sein können, eine Krankheit, die durch eine Erweiterung des Gefäßsystems gekennzeichnet ist. Des weiteren wurde gezeigt, dass BMP10, zusammen mit ENG, an der Entstehung der Präeklampsie beteiligt ist, was noch einmal zusätzlich darauf hindeutet, dass BMP9 und BMP10 in der vaskulären Homöostase involviert sind. Das Ziel dieses Projektes ist es, die Rolle von BMP9 und BMP10 im adulten Herzen und deren Funktion in der vaskulären Homöostase näher zu untersuchen und besser zu verstehen. Dazu wurde eine konstitutive BMP9-Knockoutmaus generiert, in welcher BMP10 mittels einer konditionellen Cre-Rekombinase herzspezifisch (ANF-Cre) deletiert werden kann. Unsere Versuche zeigten, dass der Verlust von BMP9 und BMP10 zu Gefäßveränderungen führt, welche die vaskuläre Homöostase negativ beeinflussen und die Herzfunktion beeinträchtigen. Darüber hinaus konnte gezeigt werden, dass BMP9 und BMP10 eine essentielle Funktion im postnatalen Herzumbau und der vaskulären Homöostase haben.

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