Platelet-derived growth factor signaling through ephrin-b2 regulates hepatic vascular structure and function.
OBJECTIVE
Cirrhosis is associated with prominent changes in sinusoidal structure and function. Although the resident pericyte in liver, the hepatic stellate cell (HSC), is well characterized in the process of fibrogenesis, signaling pathways that regulate HSC vascular function are less developed. Because pericyte populations outside the liver are increasingly being recognized as a key cell type for angiogenesis and changes in vascular structure, in this study, we explore new HSC-signaling pathways that regulate sinusoidal structure and function.


METHODS
Real-time video microscopy and quantitative software analysis of vascular tube formation were used to measure HSC angiogenesis in vitro. Platelet-derived growth factor (PDGF) and ephrin-signaling pathways were modulated using molecular and pharmacologic techniques. Complementary whole animal studies were performed to correlate in vitro findings with pericyte functions in vivo.


RESULTS
We show that PDGF promotes a phenotype of HSC evidenced by enhanced HSC-driven vascular tube formation in vitro and enhanced HSC coverage of sinusoids in vivo. This angiogenic phenotype modulates specific pericyte vascular functions including permeability and pressure regulation. Furthermore, we identify a key role for ephrin-B2 as a downstream effector of PDGF signaling.


CONCLUSIONS
These studies elucidate novel HSC-signaling pathways that regulate microvascular structure and function in liver.
Semela
David
D
GI Research Unit/Fitterman Center for Digestive Disease, Mayo Clinic, Rochester, Minnesota, USA.
Das
Amitava
A
Langer
Daniel
D
Kang
Ningling
N
Leof
Edward
E
Shah
Vijay
V
D000818:Animals; D000077214:Becaplermin; D001549:Benzamides; D002199:Capillary Permeability; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006975:Hypertension, Portal / Q000378:metabolism / Q000503:physiopathology; D007091:Image Processing, Computer-Assisted; D000068877:Imatinib Mesylate; D008099:Liver / Q000098:blood supply*; D051379:Mice; D018613:Microscopy, Confocal; D018715:Microscopy, Video; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D017082:Portal Pressure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
D001549:Benzamides; D036388:Ephrin-B2; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor