Increased survivability of ischemic skin flap tissue in Flk-1+/-mice by Pellino-1 intervention.
Reduced skin flap survival due to ischemia is a serious concern during reconstructive cosmetic surgery. The absence of VEGF and its receptors during ischemia may lead to flap failure. We identified Peli1, a 46-kDa protein, as a proangiogenic molecule and is directly regulated by VEGF. Therefore, we hypothesized that Peli1 acts downstream of Flk-1/VEGFR2 and aids in skin flap survival during ischemia.



Scratch and matrigel assays were performed to observe cell proliferation, migration, and tube formation in vitro. Western blot analysis was carried out to detect the phosphorylation of Akt (p-Akt) and MAPKAPK2 (p-MK2) in HUVECs. The translational potential of Peli1 pretreatment in the rescue of skin flap tissue was studied in vivo using Flk-1+/-mice. Animals underwent dorsal ischemic skin flap surgery, and the tissue was collected on day 12 for analysis.



Western blot analysis revealed a direct relationship between Peli1 and VEGF, as demonstrated by loss-of-function and gain-of-function studies. In addition, pretreatment with Ad.Peli1 restored the phosphorylation of Akt and MK2 and improved the migration potential of Flk-1-knockdown cells. Ad.Peli1 pretreatment salvaged the ischemic skin flap of Flk-1+/-mice by increasing blood perfusion and reducing the inflammatory response and the extent of necrosis.



Our findings reveal that Peli1 is a proangiogenic molecule that acts downstream of VEGF-Flk-1 and restores angiogenesis and enhances skin flap survivability.
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT, USA.
Chandra K
CK
Rednam
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT, USA.
Rickesha L
RL
Wilson
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT, USA.
Vaithinathan
V
Selvaraju
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT, USA.|Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury, CT, USA.
Muhammad T
MT
Rishi
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT, USA.
Mahesh
M
Thirunavukkarasu
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT, USA.|Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury, CT, USA.
Vladimir
V
Coca-Soliz
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT, USA.
Rajesh
R
Lakshmanan
Stanley J. Dudrick, Department of Surgery, Saint Mary's Hospital, Waterbury, CT, USA.
John A
JA
Palesty
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT, USA.
David W
DW
McFadden
Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health, Farmington, CT, USA.
Nilanjana
0000-0003-1585-1783
N
Maulik
D043925:Angiogenesis Inducing Agents; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007511:Ischemia; D051379:Mice; D009687:Nuclear Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D012867:Skin / Q000098:blood supply / Q000473:pathology; D013524:Surgical Flaps / Q000098:blood supply / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
D043925:Angiogenesis Inducing Agents; D009687:Nuclear Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D044767:Ubiquitin-Protein Ligases; D040301:Vascular Endothelial Growth Factor Receptor-2; C418046:Peli1 protein, mouse
Flk-1; Pellino-1; angiogenesis; distal flap necrosis; skin flap