Gastroenterology

Gastroenterology

Volume 135, Issue 2, August 2008, Pages 671-679.e2
Gastroenterology

Basic–Liver, Pancreas, and Biliary Tract
Platelet-Derived Growth Factor Signaling Through Ephrin-B2 Regulates Hepatic Vascular Structure and Function

https://doi.org/10.1053/j.gastro.2008.04.010Get rights and content

Background & Aims: 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.

Section snippets

Cell Culture

All tissue culture and transfection reagents were obtained from GIBCO (Rockville, MD). Isolated primary human HSC and primary human SEC (ScienCell Research Laboratories, Carlsbad, CA) were used between passages 2 and 6. Their phenotypic characterization has been previously described.7, 8 HSC and SEC were cultured in defined medium (ScienCell) and supplemented with 10% fetal bovine serum (where indicated), L-glutamine (1 mmol/L), penicillin (100 IU/mL), and streptomycin (100 μg/mL). In some

PDGF Promotes an Angiogenic Phenotype of HSC That Facilitates Vascular Tube Formation

In liver, HSC are best characterized by their capacity to deposit collagen matrix; other traditional functions frequently ascribed to pericytes in other organ beds are less defined in the context of HSC, including interaction with endothelial cells (EC) to form angiogenic vascular networks. To explore this concept, human HSC and human SEC were labeled with complementary vital dyes and then cocultured on Matrigel. Coculture of HSC and EC (ratio, 1:3) on Matrigel leads to formation of a vascular

Discussion

Whereas pressure regulation within the sinusoids is highly dependent on vasoregulatory mediators, the ability of the sinusoids to contract requires the generation of a critical mass of HSC that align themselves in an effective manner around the vessel lumen. This process, which we refer to as pathologic sinusoidal remodeling, requires the recruitment of “angiogenic” HSC to the vessel wall or activation of local HSC with extension of tentacle-like structures from these cells that encircle the

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    D.S. and A.D. contributed equally to this work.

    Conflicts of interest: The contributors disclose no conflicts of interest.

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