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Sandrine Levet

BMP9 and BMP10 in perinatal vascular remodeling: lymphatic development, postnatal retinal angiogenesis, closure of the ductus arteriosus and gestation. Phenotypic study of the Bmp9-KO mouse



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Published on 2 October 2013
Thesis presented October​ 02, 2013

Abstract :
BMP9 (Bone Morphogenetic Protein 9) and BMP10 are two growth factors of the TGFß family. They are both high affinity ligands for the receptor ALK1 (Activin receptor-like kinase 1), whose mutations are responsible of two vascular pathologies: Rendu-Osler disease and Pulmonary arterial hypertension. BMP10 invalidation has been described as embryonically lethal due to serious cardiac defects. BMP9 has been revealed as circulating vascular quiescence factor, but its inactivation has not been described before.
In this context, the aim of my thesis was to evaluate the respective roles of BMP9 and BMP10 in vascular remodeling. We used Bmp9-KO mice for this purpose, which were provide by S-J Lee's team from Baltimore (USA).
Although these mice are viable and fertile, we showed that they displayed abnormal lymphatic vessels characterized by vessel enlargement and reduction in number of valves, leading to a decreased lymphatic draining efficiency. Consistent with these data, we showed that BMP9 regulates expression of several genes known to be involved in lymphatic development.
In contrast, BMP9 loss-of-function didn't affect blood vessels. We demonstrated that this was due to BMP9 and BMP10 redundancy, as BMP10 neutralization in BMP9-KO pups led to a dramatic decrease in retinal vascular expansion. Theses pups also display an abnormal closure of their ductus arteriosus. This vessels diverts blood away from the non-functional lungs during fetal life and its closure is essential for postnatal survival.
Taken together, our results underlie the implication of BMP9 and BMP10 in lymphatic and blood postnatal vascular remodeling.


Keywords:
Genetics​, signalization, GTPase activating protein, Rac, Rho, Cdc42, cytoskeleton​​

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