Fig. 5.

BMP9-induced phenotypic transformation of the PAH endothelium is mediated through IL6-dependent signaling and can be therapeutically impeded. a Representative immunostaining in control and PAH MVECs after combination treatments. Stimuli were applied every 24 h for three days total. b Explanatory model. BMP9 transiently activates EndMT transcriptional signaling in MVECs. In the healthy lung ECs this response is short-lived and on the long term coincides with a downregulation of other pathways including inflammatory, hypoxic, and apoptotic signaling. In MVECs of patients with PAH the suppression of pro-inflammatory, pro-hypoxic, and pro-apoptotic signaling upon BMP9 is astray. This causes persistent EndMT signaling in PAH marked by increased levels of the EndMT master transcription factors SNAI1 and SNAI2. The loss of suppressor function is characterized by increased transcriptional levels of IL6 as well as high levels of secreted IL6. Autocrine activation of the PAH endothelium by IL6 in conjunction with the BMP9-induced EndMT program causes the diseased lung ECs to lose endothelial-specific markers, gain mesenchymal characteristics, and decrease barrier integrity. The BMP9-triggered and IL6-mediated mesenchymal change and consequent loss of barrier function can be prevented by neutralizing endothelial secreted IL6 with a capturing antibody (αIL6)