Domain-dependent action of urokinase on smooth muscle cell responses

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Domain-dependent action of urokinase on smooth muscle cell responses William J Tanski, MD, Allison J Fegley, MD, Elisa Roztocil, BS, Mark G Davies, MD, PhD Journal of Vascular Surgery Volume 39, Issue 1, Pages 214-222 (January 2004) DOI: 10.1016/S0741-5214(03)01031-0

Fig 1 A, Migration in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 n mol/L), amino-terminal fragment of uPA (ATF; 10 nmol/L), kringle (10 n mol/L), and carboxy-terminal fragment of uPA (CTF; 10 nmol/L) in the wound assay. Confluent plates were scratched, and reagents were added at time 0; cells were then allowed to migrate over 24 hours. Larger decreases in wound area (more negative values) represent increased migration. Values represent mean ± SEM percent of control for six experiments (**P < .01 vs control). B, Migration in response to sc-uPA (10 n mol/L), ATF (10 n mol/L), and kringle (10 n mol/L) in the wound assay, with and without the plasmin inhibitors ϵ-aminocaproic acid (EACA, 100 μmol/L) and aprotinin (100 units/mL). Values represent mean ± SEM of percent of control for six experiments. C, Migration response to ATF in the wound assay with and without pertussis toxin (PTx; 100 ng/mL), GP-2A (a Gαq inhibitory peptide; 10 μmol/L), or a mitogen-activated protein kinase–1 inhibitor (PD98059, PD; 25 μmol/L). Values represent mean ± SEM of percent of control for six experiments (**P < .01, ATF alone). D and E, online only. Migration response to sc-uPA (D) and kringle (E) in the wound assay with and without pertussis toxin (PTx; 100 ng/mL), a mitogen-activated protein kinase–1 inhibitor (PD98059, PD; 25 μmol/L), or GP-2A (a Gαq inhibitory peptide; 10 μmol/L). Values represent mean ± SEM of percent of control for six experiments (**P < .01 vs sc-uPA [D] and kringle [E] alone). Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)

Fig 1 A, Migration in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 n mol/L), amino-terminal fragment of uPA (ATF; 10 nmol/L), kringle (10 n mol/L), and carboxy-terminal fragment of uPA (CTF; 10 nmol/L) in the wound assay. Confluent plates were scratched, and reagents were added at time 0; cells were then allowed to migrate over 24 hours. Larger decreases in wound area (more negative values) represent increased migration. Values represent mean ± SEM percent of control for six experiments (**P < .01 vs control). B, Migration in response to sc-uPA (10 n mol/L), ATF (10 n mol/L), and kringle (10 n mol/L) in the wound assay, with and without the plasmin inhibitors ϵ-aminocaproic acid (EACA, 100 μmol/L) and aprotinin (100 units/mL). Values represent mean ± SEM of percent of control for six experiments. C, Migration response to ATF in the wound assay with and without pertussis toxin (PTx; 100 ng/mL), GP-2A (a Gαq inhibitory peptide; 10 μmol/L), or a mitogen-activated protein kinase–1 inhibitor (PD98059, PD; 25 μmol/L). Values represent mean ± SEM of percent of control for six experiments (**P < .01, ATF alone). D and E, online only. Migration response to sc-uPA (D) and kringle (E) in the wound assay with and without pertussis toxin (PTx; 100 ng/mL), a mitogen-activated protein kinase–1 inhibitor (PD98059, PD; 25 μmol/L), or GP-2A (a Gαq inhibitory peptide; 10 μmol/L). Values represent mean ± SEM of percent of control for six experiments (**P < .01 vs sc-uPA [D] and kringle [E] alone). Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)

Fig 1 A, Migration in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 n mol/L), amino-terminal fragment of uPA (ATF; 10 nmol/L), kringle (10 n mol/L), and carboxy-terminal fragment of uPA (CTF; 10 nmol/L) in the wound assay. Confluent plates were scratched, and reagents were added at time 0; cells were then allowed to migrate over 24 hours. Larger decreases in wound area (more negative values) represent increased migration. Values represent mean ± SEM percent of control for six experiments (**P < .01 vs control). B, Migration in response to sc-uPA (10 n mol/L), ATF (10 n mol/L), and kringle (10 n mol/L) in the wound assay, with and without the plasmin inhibitors ϵ-aminocaproic acid (EACA, 100 μmol/L) and aprotinin (100 units/mL). Values represent mean ± SEM of percent of control for six experiments. C, Migration response to ATF in the wound assay with and without pertussis toxin (PTx; 100 ng/mL), GP-2A (a Gαq inhibitory peptide; 10 μmol/L), or a mitogen-activated protein kinase–1 inhibitor (PD98059, PD; 25 μmol/L). Values represent mean ± SEM of percent of control for six experiments (**P < .01, ATF alone). D and E, online only. Migration response to sc-uPA (D) and kringle (E) in the wound assay with and without pertussis toxin (PTx; 100 ng/mL), a mitogen-activated protein kinase–1 inhibitor (PD98059, PD; 25 μmol/L), or GP-2A (a Gαq inhibitory peptide; 10 μmol/L). Values represent mean ± SEM of percent of control for six experiments (**P < .01 vs sc-uPA [D] and kringle [E] alone). Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)

Fig 2 A, Densitometric measurements of time-dependent extracellular signal-regulated kinase (ERK)–1/2 phosphorylation in response to carboxy-terminal fragment (CTF; 10 nmol/L) in the presence and absence of plasmin inhibitors aprotinin (100 units/mL) and ϵ-aminocaproic acid (EACA; 100 μmol/L). ERK phosphorylation is expressed as increase over time 0 control. B, C, Maximal ERK phosphorylation for single-chain urokinase-type plasminogen activator (sc-uPA; 10 nmol/L [B, C]), amino-terminal fragment of uPA (ATF; 10 nmol/L [B]), kringle (10 nM, [B]), and carboxy-terminal fragment of uPA (CTF; 10 nmol/L [C]) in the presence and absence of Gαi inhibitor pertussis toxin (PTx; 100 ng/mL) and mitogen-activated protein kinase–1 inhibitor PD98059 (PD; 25 μmol/L). All values represent mean ± SEM of percent of control for three experiments (*P < .05, **P < .01, vs agonist alone). D-F, online only. Densitometric measurements of time-dependent extracellular signal-regulated kinase (ERK)–1/2 phosphorylation in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 nmol/L [D]), amino-terminal fragment of uPA (ATF; 10 n mol/L [E]), and kringle (10 n mol/L [F]) in presence and absence of plasmin inhibitors aprotinin (100 units/mL) or ϵ-aminocaproic acid (EACA; 100 μmol/L). ERK phosphorylation is expressed as increase over time 0 control. Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)

Fig 2 A, Densitometric measurements of time-dependent extracellular signal-regulated kinase (ERK)–1/2 phosphorylation in response to carboxy-terminal fragment (CTF; 10 nmol/L) in the presence and absence of plasmin inhibitors aprotinin (100 units/mL) and ϵ-aminocaproic acid (EACA; 100 μmol/L). ERK phosphorylation is expressed as increase over time 0 control. B, C, Maximal ERK phosphorylation for single-chain urokinase-type plasminogen activator (sc-uPA; 10 nmol/L [B, C]), amino-terminal fragment of uPA (ATF; 10 nmol/L [B]), kringle (10 nM, [B]), and carboxy-terminal fragment of uPA (CTF; 10 nmol/L [C]) in the presence and absence of Gαi inhibitor pertussis toxin (PTx; 100 ng/mL) and mitogen-activated protein kinase–1 inhibitor PD98059 (PD; 25 μmol/L). All values represent mean ± SEM of percent of control for three experiments (*P < .05, **P < .01, vs agonist alone). D-F, online only. Densitometric measurements of time-dependent extracellular signal-regulated kinase (ERK)–1/2 phosphorylation in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 nmol/L [D]), amino-terminal fragment of uPA (ATF; 10 n mol/L [E]), and kringle (10 n mol/L [F]) in presence and absence of plasmin inhibitors aprotinin (100 units/mL) or ϵ-aminocaproic acid (EACA; 100 μmol/L). ERK phosphorylation is expressed as increase over time 0 control. Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)

Fig 2 A, Densitometric measurements of time-dependent extracellular signal-regulated kinase (ERK)–1/2 phosphorylation in response to carboxy-terminal fragment (CTF; 10 nmol/L) in the presence and absence of plasmin inhibitors aprotinin (100 units/mL) and ϵ-aminocaproic acid (EACA; 100 μmol/L). ERK phosphorylation is expressed as increase over time 0 control. B, C, Maximal ERK phosphorylation for single-chain urokinase-type plasminogen activator (sc-uPA; 10 nmol/L [B, C]), amino-terminal fragment of uPA (ATF; 10 nmol/L [B]), kringle (10 nM, [B]), and carboxy-terminal fragment of uPA (CTF; 10 nmol/L [C]) in the presence and absence of Gαi inhibitor pertussis toxin (PTx; 100 ng/mL) and mitogen-activated protein kinase–1 inhibitor PD98059 (PD; 25 μmol/L). All values represent mean ± SEM of percent of control for three experiments (*P < .05, **P < .01, vs agonist alone). D-F, online only. Densitometric measurements of time-dependent extracellular signal-regulated kinase (ERK)–1/2 phosphorylation in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 nmol/L [D]), amino-terminal fragment of uPA (ATF; 10 n mol/L [E]), and kringle (10 n mol/L [F]) in presence and absence of plasmin inhibitors aprotinin (100 units/mL) or ϵ-aminocaproic acid (EACA; 100 μmol/L). ERK phosphorylation is expressed as increase over time 0 control. Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)

Fig 2 A, Densitometric measurements of time-dependent extracellular signal-regulated kinase (ERK)–1/2 phosphorylation in response to carboxy-terminal fragment (CTF; 10 nmol/L) in the presence and absence of plasmin inhibitors aprotinin (100 units/mL) and ϵ-aminocaproic acid (EACA; 100 μmol/L). ERK phosphorylation is expressed as increase over time 0 control. B, C, Maximal ERK phosphorylation for single-chain urokinase-type plasminogen activator (sc-uPA; 10 nmol/L [B, C]), amino-terminal fragment of uPA (ATF; 10 nmol/L [B]), kringle (10 nM, [B]), and carboxy-terminal fragment of uPA (CTF; 10 nmol/L [C]) in the presence and absence of Gαi inhibitor pertussis toxin (PTx; 100 ng/mL) and mitogen-activated protein kinase–1 inhibitor PD98059 (PD; 25 μmol/L). All values represent mean ± SEM of percent of control for three experiments (*P < .05, **P < .01, vs agonist alone). D-F, online only. Densitometric measurements of time-dependent extracellular signal-regulated kinase (ERK)–1/2 phosphorylation in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 nmol/L [D]), amino-terminal fragment of uPA (ATF; 10 n mol/L [E]), and kringle (10 n mol/L [F]) in presence and absence of plasmin inhibitors aprotinin (100 units/mL) or ϵ-aminocaproic acid (EACA; 100 μmol/L). ERK phosphorylation is expressed as increase over time 0 control. Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)

Fig 3 A-D, Representative Western blots of extracellular signal-regulated kinase (ERK)–1/2 phosphorylation in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 n mol/L [A]), amino-terminal fragment (ATF; 10 n mol/L [B]), kringle (10 n mol/L [C]), and carboxy-terminal fragment (CTF; 10 n mol/L [D]) in the presence and absence of the plasmin inhibitors aprotinin (100 units/mL) and ϵ-aminocaproic acid (EACA; 100 μmol/L), Gαi inhibitor pertussis toxin (PTx; 100 ng/mL), and mitogen-activated protein kinase–1 inhibitor PD98059 (25 μmol/L). P44, Phosphorylated form of ERK2; p42, phosphorylated form of ERK1. Cells were pretreated with inhibitors for 30 minutes. Blots are representative of three experiments for each time course. Bands labeled with agonists (eg, uPA) or inhibitors (eg, pertussis toxin) represent positive and negative controls, respectively. Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)

Fig 3 A-D, Representative Western blots of extracellular signal-regulated kinase (ERK)–1/2 phosphorylation in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 n mol/L [A]), amino-terminal fragment (ATF; 10 n mol/L [B]), kringle (10 n mol/L [C]), and carboxy-terminal fragment (CTF; 10 n mol/L [D]) in the presence and absence of the plasmin inhibitors aprotinin (100 units/mL) and ϵ-aminocaproic acid (EACA; 100 μmol/L), Gαi inhibitor pertussis toxin (PTx; 100 ng/mL), and mitogen-activated protein kinase–1 inhibitor PD98059 (25 μmol/L). P44, Phosphorylated form of ERK2; p42, phosphorylated form of ERK1. Cells were pretreated with inhibitors for 30 minutes. Blots are representative of three experiments for each time course. Bands labeled with agonists (eg, uPA) or inhibitors (eg, pertussis toxin) represent positive and negative controls, respectively. Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)

Fig 4 A and B, In vitro [3H]- thymidine incorporation into DNA of cultured rat vascular smooth muscle cells in response to 0.1 to 100 n mol/L of single-chain urokinase-type plasminogen activator (sc-uPA), carboxy-terminal fragment of uPA (CTF), amino-terminal fragment of uPA (ATF), and kringle. B represents results for each agonist at 10 n mol/L. Values represent mean ± ± SEM of increase over control for four experiments (**P < .01 vs control). C, Cell proliferation in response to sc-uPA (10 n mol/L) and CTF (10 n mol/L) as measured by cell counting. ATF and kringle at 10 n mol/L did not stimulate cell proliferation (data not shown). Reagents were added at time 0. Serum (10%) and DMEM represent positive and negative controls, respectively. Values represent mean ± SEM of increase over control for six experiments. Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)

Fig 5 A, In vitro [3H]-thymidine incorporation into DNA of cultured rat vascular smooth muscle cells over 24 hours in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 n mol/L) and carboxy-terminal fragment of uPA (CTF; 10 n mol/L) in the presence and absence of plasmin inhibitors aprotinin (100 units/mL) and ϵ-aminocaproic acid (100 μmol/L). Values represent mean ± SEM of percent of control for five experiments (**P < .01 vs sc-uPA or CTF alone). B, In vitro [3H]-thymidine incorporation into DNA of cultured rat vascular smooth muscle cells over 24 hours in response to CTF (10 n mol/L) in the presence and absence of the Gαi inhibitor pertussis toxin (PTx; 100 ng/mL), mitogen-activated protein kinase–1 inhibitor PD98059 (25 μmol/L), and Gαq inhibitory peptide GP-2A (10 μmol/L). Values represent mean ± SEM of percent of control for six experiments (**P < .01 vs CTF alone). C, online only. In vitro [3H]-thymidine incorporation into DNA of cultured rat vascular smooth muscle cells over 24 hours in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 n mol/L) in the presence and absence of the Gαi inhibitor pertussis toxin (PTx; 100 ng/mL), mitogen-activated protein kinase inhibitor PD98059 (25 μmol/L), and Gαq inhibitory peptide GP-2A (10 μmol/L). Values represent mean ± SEM of percent of control for six experiments (**P < .01 vs sc-uPA alone). Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)

Fig 5 A, In vitro [3H]-thymidine incorporation into DNA of cultured rat vascular smooth muscle cells over 24 hours in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 n mol/L) and carboxy-terminal fragment of uPA (CTF; 10 n mol/L) in the presence and absence of plasmin inhibitors aprotinin (100 units/mL) and ϵ-aminocaproic acid (100 μmol/L). Values represent mean ± SEM of percent of control for five experiments (**P < .01 vs sc-uPA or CTF alone). B, In vitro [3H]-thymidine incorporation into DNA of cultured rat vascular smooth muscle cells over 24 hours in response to CTF (10 n mol/L) in the presence and absence of the Gαi inhibitor pertussis toxin (PTx; 100 ng/mL), mitogen-activated protein kinase–1 inhibitor PD98059 (25 μmol/L), and Gαq inhibitory peptide GP-2A (10 μmol/L). Values represent mean ± SEM of percent of control for six experiments (**P < .01 vs CTF alone). C, online only. In vitro [3H]-thymidine incorporation into DNA of cultured rat vascular smooth muscle cells over 24 hours in response to single-chain urokinase-type plasminogen activator (sc-uPA; 10 n mol/L) in the presence and absence of the Gαi inhibitor pertussis toxin (PTx; 100 ng/mL), mitogen-activated protein kinase inhibitor PD98059 (25 μmol/L), and Gαq inhibitory peptide GP-2A (10 μmol/L). Values represent mean ± SEM of percent of control for six experiments (**P < .01 vs sc-uPA alone). Journal of Vascular Surgery 2004 39, 214-222DOI: (10.1016/S0741-5214(03)01031-0)