Integrating the VEGF Signals Leading to Actin-Based Motility in Vascular Endothelial Cells

UPARANT: A Urokinase Receptor–Derived Peptide Inhibitor of VEGF-Driven Angiogenesis with Enhanced Stability and In Vitro and In Vivo Potency

“…Twelve female New Zealand White rabbits (Charles River) weighing 2.5 to 3.0 kg were anesthetized by intramuscular injection of acepromazina (1 mg/kg), ketamine hydrochloride (35 mg/kg), and xylazine hydrochloride (5 mg/kg) and 3 to 4 drops of 0,4% ossibuprocain chlorohydrate solution were topically applied to the eye before micropocket surgery. A wire speculum was positioned in the eye, and a sucralfatehydron pellets containing PBS, 5 mg UPARANT, or 180 ng VEGF with/without 5 mg UPARANT were implanted into the cornea after making a micropocket in the stroma, using standard surgical tools (25,26). Tobradex (0.3% tobramycin-0.1% dexamethasone) was applied to the surface of the cornea after pellet implantation to prevent infection.…”

The vitamin K–dependent anticoagulant factor, protein S, inhibits multiple VEGF-A–induced angiogenesis events in a Mer- and SHP2-dependent manner

“…The angiogenic effect of VEGF-A is in part the result of its ability to stimulate EC motility, which is an important step of vascular pattern formation. 32 Therefore, we evaluated the ability of human ProS to interfere with VEGF-A-induced ECs directional migration. At 10 g/mL, human ProS inhibited chemotaxis induced by 20 ng/mL VEGF-A by Ͼ 50% (Figure 3D).…”

VEGF121 and VEGF165 Regulate Blood Vessel Diameter Through Vascular Endothelial Growth Factor Receptor 2 in an in vitro Angiogenesis Model

“…Signaling through VEGFR-2 promotes both cell survival and cell proliferation (Gerber et al, 1998; Gratton Rousseau et al, 2000). Numerous downstream targets of VEGFR-2 are known to be phosphorylated upon activation of the receptor, including phosphatidylinositol 3-kinase (PI3K), MAP and ERK Kinase-1 (MEK-1), p38 mitogen-activated protein kinase (MAPK), phospholipase C-␥ (PLC-␥), Ras GTPase-activating protein, and several others (Bernatchez et al, 2001;Gerber et al, 1998;Meadows et al, 2001;Rousseau et al, 2000;Takahashi et al, 1999).…”

“…Numerous downstream targets of VEGFR-2 are known to be phosphorylated upon activation of the receptor, including phosphatidylinositol 3-kinase (PI3K), MAP and ERK Kinase-1 (MEK-1), p38 mitogen-activated protein kinase (MAPK), phospholipase C-␥ (PLC-␥), Ras GTPase-activating protein, and several others (Bernatchez et al, 2001;Gerber et al, 1998;Meadows et al, 2001;Rousseau et al, 2000;Takahashi et al, 1999). It is possible that the increased diameter of vessels in response to higher concentrations of VEGF represents a graded response of second messenger pathways to increased VEGFR-2 signaling.…”

“…PI3K and its immediate target, Akt, are wellcharacterized downstream effectors of VEGFR-2 signaling (Gerber et al, 1998;Rousseau et al, 2000) and have been reported to mediate enhanced EC survival, a possible explanation for enhanced EC numbers at higher levels of VEGF, so we looked for Akt activation in narrow tubes-cultured in 2.5 ng/ml of VEGF-and in wider tubes-cultured in 15 ng/ml of VEGF. As seen in Figure 6B, phospho-Akt is detectable at low concentrations of VEGF, and its level is increased at higher concentrations, as expected.…”