Previous studies have suggested that the Notch signaling pathway plays a very important role in the proliferation and differentiation of pulmonary microvascular endothelial cells (PMVECs). Therefore, we aimed to investigate the expression level of Notch-related signaling molecules in PMVECs in bleomycin (BLM)-induced rat pulmonary fibrosis. Immunohistochemistry, immunofluorescence, Western blotting, and real-time PCR were used to analyze the differences in protein and mRNA expression levels of Notch-related signaling molecules, i.e. Notch1, Jagged1, Delta-like ligand 4 (Dll4), and hairy and enhancer of split homolog 1 (Hes1), between a control group treated with intratracheal instillation of saline and a study group treated with intratracheal instillation of BLM solution. Expression levels of the receptor Notch1 and one of its ligands, Jagged1, were upregulated, while the expression levels of the ligand Dll4 and the target molecule of the Notch signaling pathway, Hes1, were downregulated. The differences in protein and mRNA expression levels between the control and study groups were significant (p<0.001). The Jagged1/Notch1 signaling pathway is activated in the pathogenesis of BLM-induced rat pulmonary fibrosis, while the Dll4/Notch1 signaling pathway is inhibited, which inhibits the suppressive effect of Dll4/Notch1 signaling on PMVEC overproliferation, further causing PMVEC dysfunction in cell sprouting and maturation as well as abnormal differentiation of the cell phenotype. Conversely, the down-expression of Hes1 indicates that the Jagged1/Notch1 signaling pathway could be a non-canonical Notch signaling pathway independent of Hes1 activation, which differs from the canonical Dll4/Notch1 signaling pathway.

• MeSH
• Pulmonary Artery drug effects   metabolism   MeSH
• Bleomycin MeSH
• Endothelial Cells drug effects   metabolism   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Intercellular Signaling Peptides and Proteins metabolism   MeSH
• Microvessels metabolism   MeSH
• Pulmonary Fibrosis chemically induced   metabolism   MeSH
• Receptors, Notch metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Nádorová angiogeneze představuje pro nádorové buňky účinný mechanizmus vlastního přežití a šíření se do vzdálených tkání. Není proto překvapením, že se antiangiogenní strategie široce studuje a uplatňuje v léčbě. Po prvních klinicky používaných molekulách, jež působí v oblasti receptoru pro vaskulární epiteliální růstový faktor (VEGFR) ať již vyvázáním VEGF, či inhibicí intracelulární domény VEGFR se pozornost vědců obrací k dalším cílům, které jsou součástí angiogenních kaskád (proteiny TIE, VHL a další).

Tumor angiogenesis represents efficient mechanism that allows survival of tumor cells and promotes tumor growth. Antiangiogenic strategies are widely tested in various tumor types. The initial therapeutic attempts were focused on the inhibition of vascular epithelial growth factor signalling cascade and now research continues on other angiogenic signalling pathways (Tie, FGF).

• Keywords
• VEGF, TIE, angiopoietin, DLL4,
• MeSH
• Drug Resistance, Neoplasm physiology   drug effects   MeSH
• Financing, Organized MeSH
• Angiogenesis Inhibitors administration & dosage   pharmacology   MeSH
• Neoplasms drug therapy   blood supply   MeSH
• Neovascularization, Pathologic etiology   drug therapy   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Receptors, Vascular Endothelial Growth Factor drug effects   MeSH
• Vascular Endothelial Growth Factors antagonists & inhibitors   drug effects   MeSH