ERK1/2-Dependent Vascular Endothelial Growth Factor Signaling Sustains Cyst Growth in Polycystin-2 Defective Mice

Abstract

BACKGROUND & AIMS-Severe polycystic liver disease can complicate adult dominant polycystic kidney disease, a genetic disease caused by defects in polycystin-1 (Pkd1) or polycystin-2 (Pkd2). Liver cyst epithelial cells (LCECs) express vascular endothelial growth factor (VEGF) and its receptor, VEGFR-2. We investigated the effects of VEGF on liver cyst growth and autocrine VEGF signaling in mice with Pkd1 and Pkd2 conditional knockouts.

Aquaporin-1 Promotes Angiogenesis, Fibrosis, and Portal Hypertension Through Mechanisms Dependent on Osmotically Sensitive MicroRNAs

“…Indeed, most strategies targeting angiogenic molecules have shown benefit in preclinical animal models of liver disease. 11,[31][32][33][34] In this context, our study extends the current knowledge of an emerging anti-angiogenic target, AQP1, by providing direct in vivo evidence that AQP1 regulates the angiogenesis, fibrosis, and portal hypertension that occurs after BDL; and defining a novel, molecular, fine-tuning mechanism involving osmotically sensitive miRs that may contribute to the pathological overexpression of AQP1 during cirrhosis. We previously demonstrated that AQP1 is overexpressed in the angiogenic neovasculature within fibrotic septa in human cirrhosis and in CCl 4 -induced liver injury in C57 black mice.…”

Biliary Infection May Exacerbate Biliary Cystogenesis Through the Induction of VEGF in Cholangiocytes of the Polycystic Kidney (PCK) Rat

“…14,16,17 Liver cyst fluid of autosomal dominant PKD contains elevated levels of VEGF, and the cyst fluid induces vascular endothelial cell proliferation. 18,19 The contribution of signaling pathways involving ERK1/2 and mammalian target of rapamycin has been implicated in liver cyst progression of autosomal dominant PKD.…”

Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response

“…Mouse macrophages were isolated and maintained as previously described (36). Mouse primary cholangiocytes were provided by Carlo Spirli (Yale University) as previously described (37). All cell cultures were treated with indicated chemicals and collected within 96 hours after isolation.…”