BMP9/BMP10/ALK1 pathway: a new mechanism for immunomodulation in vascular diseases – BUILD

Blood vessels and lymphatic vessels are the major transit ways for immune cells, granting access to all peripheral tissues and immune storage sites in lymphoid organs. Emerging evidence from single cell RNA sequencing (scRNA-seq) suggests that specific subtypes of endothelial cells play distinct immunomodulatory roles, specific to their vascular bed. Deciphering the mechanisms driving these immunomodulatory endothelial cells could have an impact on a wide range of diseases. For example, vascular diseases such as Hereditary Hemmorhagic Telangiectasia (HHT) and Pulmonary Arterial Hypertension (PAH) are thought to be triggered or aggravated by inflammation.

Mutations in genes involved in the BMP9/BMP10/ALK1 signaling pathway are associated with HHT and PAH. We recently obtained data from phosphoproteomics and RNA sequencing suggesting that BMP9 and BMP10 can have a direct immunomodulatory effect in endothelial cells. We also observed liver and lung inflammation in knockout mouse models lacking BMP9 and BMP10. I propose to study the immunomodulatory role of the BMP9/BMP10/ALK1 signaling pathway, and its consequences in vascular diseases, especially in HHT. Based on preliminary data, the hypothesis is that BMP9 and BMP10 reduce the response to inflammatory cytokines. I intend to determine the organs and cell types involved and to decipher the molecular mechanisms. The hypothesis will be tested in advanced in vitro models (organ-on-chip), using cells from healthy donors and from patients with HHT. The hypothesis will be validated in vivo using transgenic mouse models. This project will lead to the identification of new therapeutic opportunities for HHT. The findings could be extended to other vascular diseases and will be relevant to the field of vascular biology in general.