Coordinated induction of VEGF receptors in mesenchymal cell types during rat hepatic wound healing

Abstract

Homology PCR has been used to identify receptor tyrosine kinases (RTKs) expressed during activation of rat hepatic stellate cells, the key fibrogenic mesenchymal element in the liver. Partial cDNAs encoding several RTKs were cloned from stellate cells activated in vivo, including those of Flt-1, Flk-1, c-met, PDGFR, and Tyro10/DDR2. RNAse protection from cells activated in vivo demonstrated biphasic induction of flt-1 and flk-1 mRNAs, receptors for vascular endothelial growth factor (VEGF). Culture-activation of stellate cells was associated with increased [125I]VEGF binding and Flt-1 and Flk-1 receptor protein. Induction of VEGF binding sites correlated with an 2.5-fold increase in DNA synthesis in response to VEGF, but only if cells were activated by growth on collagen 1, whereas cells maintained in a quiescent state on a basement membrane-like substratum (EHS matrix) were nonproliferative. In both stellate and endothelial cells VEGF-induced mitogenesis was augmented by co-incubation with basic fibroblast growth factor (bFGF), a cytokine with known synergy with VEGF. These findings suggest that the cellular targets of VEGF in liver may not be confined to sinusoidal endothelial cells, and that VEGF responses reflect combined effects on both hepatic stellate cells and sinusoidal endothelium.

Hepatocyte Transplantation Activates Hepatic Stellate Cells With Beneficial Modulation of Cell Engraftment in the Rat *

“…23 Among HSC-related genes expressed after cell transplantation, VEGF activates HSC and induces HSC proliferation. 24,25 Our observation of VEGF mRNA expression here was in agreement with that of previous immunostaining studies showing VEGF expression within a few hours after cell transplantation. 1 TGF-␤, which was upregulated early after cell transplantation, plays roles in activating HSC during liver fibrosis.…”

Role of free radicals in liver diseases

“…Currently, the bulk of evidence supports their origin from either the endoderm or the septum transversum, as it forms from cardiac mesenchyme during invagination of the hepatic bud [18]. A separate issue pertains to whether stellate cells and sinusoidal endothelial cells derive from a common precursor cell, a likely possibility given their shared mesenchymal phenotype, close proximity in situ, and joint expression of some angiogenic factors, for example, vascular endothelial cell growth factor [19].…”

Angiogenesis in chronic inflammatory liver disease

“…43 VEGF effects are not confined to sinusoidal ECs and hepatocytes because hepatic stellate cells can also proliferate in response to this growth factor. 44,45 Hepatic expression of Ang-1 and Ang-2 is increased following PH in rats, but at a later phase than VEGF. 37 Both factors exert opposing actions: in the presence of VEGF, Ang-2 seems to augment angiogenesis early during regeneration, while in the absence of VEGF, Ang-2 inhibits vascular growth at later stages.…”

“…2,[15][16][17][18][19] Activated hepatic stellate cells also proliferate in response to hypoxia-induced VEGF, thereby participating in nonpathological hepatic angiogenesis. [43][44][45] (Center right) Signaling pathways that determine branching, formation of adequate basement membrane and ECM, and cell migration and differentiation are then activated. This results in the assembling of ECs in tubular structures that form an organized 3-dimensional (3-D) network with defined arteriovenous boundaries and carefully regulated diameter and length.…”