Fig. 3.

VEGF-A signalling in PLD-ADPKD (working model).

In PC2-defective cholangiocytes, stimulation of cAMP production drives the PKA-dependent activation of ERK1/ERK2 and the secretion of VEGF-A (1). In turn, cAMP activates the PKA–Ras–Raf–ERK pathway and stimulates VEGF-A production through an mTOR–HIF1α-mediated mechanism (2). mTOR has a central role in IGF-1-stimulated proliferation of cystic cholangiocytes. IGF-1, a growth factor secreted by the cystic epithelium and by stressed biliary epithelial cells, binds to its receptor IGF1-R and activates the PI3K/AKT/mTOR pathway; thus, mTOR stimulates proliferation through a HIF1-α/VEGF-dependent autocrine loop (3). Furthermore, VEGF-A produced by cystic cholangiocytes increases, through a paracrine route, the periductal microvascular density and bile ducts proliferation by binding to VEGFR-2. ADPKD, autosomal dominant polycystic kidney disease; HIF1α, hypoxia-inducible factor type 1α; IGF-1, insulin-like growth factor 1; IGF1-R, insulin-like growth factor 1 receptor; mTOR, mammalian target of rapamycin; PC2, polycystin-2; PLD, polycystic liver disease; VEGF-A, vascular endothelial growth factor type A; VEGFR-2, vascular endothelial growth factor receptor type 2.