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. Author manuscript; available in PMC: 2020 Oct 22.
Published in final edited form as: Circulation. 2019 Aug 29;140(17):1409–1425. doi: 10.1161/CIRCULATIONAHA.119.040629

Figure 8. Pathogenic endothelial signaling in ‘two-hit’ model of disease.

Figure 8.

TGFβ1 and BMP9-mediated signaling are compared with and without 5-LO-mediated inflammation. (BMP9 is the principal high-affinity ligand for canonical BMPR2 signaling.4) BMPR2 insufficiency creates a proclivity for enhanced canonical and noncanonical TGFβ signaling, and increased 5-LO nucleoplasmic expression. 5-LO-mediated inflammation activates SMAD2/3-dependent canonical and p38-dependent noncanonical TGF-β pathways, inhibits SMAD1/5/9-mediated BMPR2 signaling, augments 5-LO nuclear envelope translocation for endogenous LTB4 synthesis and promotes PAEC pathological transformation.