Knockdown of Gab1, shp2, or PKA in HUVECs led to defective VEGF signaling and tube formation. Fives days after infection, shRNA-expressing HUVECs were serum-starved and stimulated with VEGF (50 ng/mL) for indicated time periods, followed by immunoblot analysis (A and B), NO release measurement (C), or tube formation assay (D and E). (A) Immunoblots of phosphorylations of eNOS, Akt, Erk1/2, AMPK and PKA substrate, and Gab1 in HUVECs expressing scrambled or Gab1 shRNAs. The differences in P-eNOS and P-Akt levels of Gab1 and scrambled shRNA-expressing groups were significant (P < 0.02). (B) Immunoblots of phosphorylations of eNOS, Akt and PKA substrate, and Akt, Shp2, PKA Cα, and PKA Cβ in HUVECs expressing scrambled, Shp2, PKA (α and β), or Akt shRNAs. The differences in P-eNOS and P-Akt levels of Shp2, PKA (α and β), or Akt shRNA-expressing groups were significant compared with scrambled control (P < 0.01). (C) Results of NO release measurement of HUVECs expressing scrambled, Gab1, shp2, PKA, or Akt shRNAs after VEGF stimulation. (D and E) Tube formation analysis of HUVECs expressing scrambled or gene-specific shRNAs of Gab1, shp2, PKA, or Akt pretreated with or without L-NAME (5 mM) or PKI (10 μM) (D) before VEGF stimulation. Asterisks indicate statistical significance (*P < 0.05, **P < 0.01) for EGKO versus control.