This observation supports the idea that the acquisition of an angiogenic phenotype by HSCs, in response to PlGF, causes an increase in the HSC population in early phase of cirrhosis that correlates with the degree of fibrosis. However, when the HSC population reaches a critical mass, the therapeutic efficiency of PlGF blockade is limited, because PlGF does not have any effect on the regulation of profibrogenic genes. In agreement with this hypothesis, it has been shown that the expression of angiogenic factors in fibrotic/cirrhotic livers occurs mainly in areas of active fibrogenesis and not in larger bridging septae or

in end-stage cirrhotic tissue.21 Therefore, this evidence points to a therapeutic window during which αPlGF treatment is effective IWR-1 solubility dmso buy ACP-196 at inhibiting and reducing fibrosis. The sustained ERK activation in response to PlGF in HSCs prompted us to investigate the underlying mechanisms, because VEGFR1 has a relatively weak tyrosine kinase activity. Some authors also have suggested that VEGFR1 could function as a decoy receptor for VEGF-A, thereby amplifying

the activity of VEGF.12 However, HSCs did not express detectable levels of VEGFR2, suggesting that VEGFR1′s role extends beyond a mere decoy activity. Comparison of the protein tyrosine phosphorylation profile of activated HSCs showed that PlGF induced the phosphorylation of other tyrosine kinase receptors, including PDGFRA and epidermal growth factor

receptor. These findings raise the intriguing possibility that upon PlGF activation, VEGFR1 may amplify its own signaling by highjacking other RTKs via a molecular association. In our initial analysis, we identified PDGFRA as a candidate of such molecular cross-talk that may further potentiate sustained ERK activation. A similar cross-talk between VEGFR1 and VEGFR2, whereby PlGF amplifies VEGF-driven angiogenesis, has been documented in endothelial cells.22 VEGFR1 also interacts with low-density lipoprotein receptor, that results in ligand-independent activation of VEGFR1 by LDL.23 However, a molecular cross-talk between VEGFR1 and other types of RTKs, resulting in sustained signaling, has never been 上海皓元 documented yet. Although antiangiogenic agents are frequently used in the treatment of angiogenesis-related diseases, their clinical use has been associated with adverse effects, such as hypertension, proteinuria, thrombosis, and reduced wound healing capacity. These adverse effects warrant some caution to select angiogenic inhibitors for the treatment of patients with cirrhosis who are critically ill. Studies in transgenic mice have shown that loss of PlGF does not affect development, reproduction, or normal postnatal health, but impairs pathological angiogenesis in implanted and spontaneously arising cancer models.