title: Angiogenesis within the duodenum of patients with cirrhosis is modulated by mechanosensitive Kruppel-like factor 2 and microRNA-126.
abstract: BACKGROUND
  The mechanism involved in neovascularization in splanchnic circulation and the main trigger that induces angiogenesis in patients with cirrhosis are not fully recognized.
  
  
  OBJECTIVE
  To explore the involvement of flow sensitive lung Kruppel-like factor (KLF2), microRNA-126 (miR-126), angiopoietin-2 (Ang-2) and heme oxygenase-1 (HO-1) in modulation of vascular endothelial growth factor (VEGF) signalling that have a critical effect on growth of new blood vessels.
  
  
  METHODS
  Duodenal biopsies from 22 patients with cirrhosis and 10 controls were obtained during routine endoscopy. The process of angiogenesis was evaluated by a measurement of CD31 concentration, immunodetection of CD34 protein and estimation of capillary densities. Messenger RNA (mRNA) and protein expressions were analysed by real-time PCR, Western blot or ELISA respectively.
  
  
  RESULTS
  Markers of angiogenesis (both, CD31 and CD34) were significantly enhanced in cirrhotic patients. In comparison to healthy controls, levels of Ang-2 and KLF-2 mRNAs as well as Ang-2, KLF-2, HO-1, VEGF protein expressions were considerably increased. Levels of sCD163, a surrogate marker of portal hypertension, correlated with levels of Ang-2, (P = 0.021) and VEGF (P = 0.009). The expression of miR-126, a KLF2-mediated regulator of the VEGF signalling was enhanced in cirrhotic patients.
  
  
  CONCLUSIONS
  Our results demonstrate, for the first time in humans, that neovascularization is induced in duodenal tissue of patients with cirrhosis and proangiogenic factors such as KLF-2, Ang-2, miR-126 and VEGF can contribute to the angiogenesis induced by hemodynamic forces. Thus, cirrhosis-induced blood flow and pressure within splanchnic vessels may be important hemodynamic triggers that initiate the angiogenic signalling cascade.
authors.affiliation: Medical Biology Laboratory, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kobus
authors.forename: Justyna
authors.initials: J
authors.lastname: Kopycinska
authors.forename: Anna
authors.initials: A
authors.lastname: Kozlowska-Wiechowska
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Urasinska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kempinska-Podhorodecka
authors.forename: Tara L
authors.initials: TL
authors.lastname: Haas
authors.forename: Piotr
authors.initials: P
authors.lastname: Milkiewicz
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Milkiewicz
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D004386:Duodenum / Q000098:blood supply*; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D006975:Hypertension, Portal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013152:Splanchnic Circulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1