Indeed, while research has shown that hyperinsulinemia mediates pathologic angiogenesis through the proliferative actions of the ERK MAPK pathway (42, 43), chronically elevated levels of insulin may also trigger the expression of EPDR1 and potentially many others through the endoglin/ALK1/Smad1/5 signaling axis. This evidence concerns the gene SMAD1 and hyperinsulinism.