Research project: The Immunomodulatory Role of BMP9 and BMP10 Signaling in Endothelial Cells
Supervisors: Dr. Sabine Bailly & Dr. Claire Bouvard
Endothelial cells constitute the inner lining of the blood vessels and are the site of action of circulating molecules that coordinate systemic responses. BMP9 and BMP10 are two circulating factors belonging to the TGFβ family of proteins and are responsible for vascular quiescence and homeostasis. However, the role of BMP9 and BMP10 in modulating endothelial cell activation and endothelial-immune interaction in physiological and inflammatory contexts is still unclear.
The “BAL” team (BMPs in angiogenesis and lymphangiogenesis, BioSanté, INSERM/UGA/CEA-Grenoble) works on transgenic mice that are knockout for BMP9 or BMP10 or both (DKO). Some of these mice exhibit an inflammatory phenotype of unknown origin. Also, phosphoproteomic analysis highlights a potential cross talk between the BMP9/BMP10 pathway and the JAK-STAT3 pathway in endothelial cells. Therefore, the objective of my internship was to decipher the cross talk between these two pathways and to better characterize the inflammatory phenotype of the knockout mice.
We were able to show for the first time that BMP9 and BMP10 can modulate inflammation and play an immunomodulatory role in endothelial cells. Using in vitro assays, we found that BMP9 and BMP10 have the capacity to partially inhibit the phosphorylation of pSTAT3 induced by IL-6 in human umbilical vein endothelial cells. Furthermore, we showed that this mechanism is dependent on the canonical SMAD pathway that induces SOCS3, a negative regulator of the JAK-STAT3 pathway. In vivo, we demonstrated that mice lacking BMP9 and BMP10 and exhibiting lung inflammation of unknown origin, have high pSTAT3 levels in the lungs and elevated levels of circulating chemoattractant factors suggesting an aberrant activation.
Together, our results demonstrate that BMP9 and BMP10 can play an immunomodulatory role in endothelial cells in vitro and in
vivo, though the in vivo mechanism remains to be determined. These observations might constitute the starting point of studies aiming to make use of this immunomodulatory property to target vascular pathologies such as Rendu-Osler disease and pulmonary arterial hypertension, where inflammation is suspected to contribute to the pathogenesis.
Mohamad is now pursuing a PhD at IGMM in Montpellier under the supervision of Dr. Daniel Fisher.