Fig. 5.

Proposed blocking action of gremlin 1 on both BMP and VEGF signaling during the development of hypoxic pulmonary hypertension (HPH). As confirmed in the present study, the canonical action of increased gremlin 1 during the development of HPH is to prevent BMP2 and BMP4 binding to BMPRs thus blocking BMP dependent signaling. Increased gremlin 1 simultaneously acts to block VEGF signaling by binding to VEGFR2.⁵³ Reduced BMPR signaling^74,75 and reduced VEGFR2 signaling^23,65 both contribute importantly to the development of HPH. Thus, gremlin 1 mediated blockade of both pathways causes vasoconstriction and vascular remodeling. The signaling pathways illustrated in the schematic are only those used in the present study to demonstrate the separate blocking actions of gremlin 1 on BMPR signaling and on VEGFR2 signaling. Both agonists also exert multiple other actions that are not shown here.