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Kallikrein gene-modified EPCs induce angiogenesis in rats with ischemic hindlimb and correlate with integrin αvβ3 expression.

Fu SS, Li FJ, Wang YY, You AB, Qie YL, Meng X, Li JR, Li BC, Zhang Y, Da Li Q - PLoS ONE (2013)

Bottom Line: Expressions of integrin αvβ3 and endothelial nitric oxide synthase (eNOS) were detected on the surface of EPCs.The levels of integrin αvβ3 expression were reduced by PI3K and eNOS blockade, and the inhibitor of integrin αvβ3 abrogated the migration and adhesion of hTK-transduced EPCs (P<0.05). hTK gene delivery in vivo improves the natural angiogenic response to ischemia.The ability of hTK gene-transduced EPCs can be enhanced in vitro, in which integrin αvβ3 plays a role in the process.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.

ABSTRACT

Background: Human tissue kallikrein (hTK) plays an essential role in the physiological and pathological mechanisms of blood vessels. This study aimed to determine whether angiogenesis induced by endothelial progenitor cells (EPCs) transduced with the adenovirus-mediated hTK gene could improve blood flow in rat hindlimb ischemia in vivo and to establish a promising mechanism in vitro.

Methods: EPCs transduced with adenovirus encoding hTK-162 (i.e., Ad/hTK-transduced EPCs or Ad/GFP-transduced EPCs) were administered to Wister rats with hindlimb ischemia through therapeutic neovascularization. Muscular capillary density (MCD), blood flow (BF), and the number of myofibers were measured at days 7, 14, and 21 after treatment. Expressions of integrin αvβ3 and endothelial nitric oxide synthase (eNOS) were detected on the surface of EPCs.

Results: MCD, BF, and the number of myofibers in rats with Ad/hTK-transduced EPCs remarkably increased at day 21 after treatment compared with rats with Ad/GFP-transduced EPCs or the control group (P<0.01). Expressions of integrin αvβ3 and eNOS protein on the surface of EPCs also increased in rats with Ad/hTK-transduced EPCs. The levels of integrin αvβ3 expression were reduced by PI3K and eNOS blockade, and the inhibitor of integrin αvβ3 abrogated the migration and adhesion of hTK-transduced EPCs (P<0.05).

Conclusion: hTK gene delivery in vivo improves the natural angiogenic response to ischemia. The ability of hTK gene-transduced EPCs can be enhanced in vitro, in which integrin αvβ3 plays a role in the process.

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Inhibition of αvβ3 expression and the migration ability of EPCs.The inhibition of αvβ3 expression can lower the migration ability of EPCs. A: Representative macroscopic photographs of Ad/hTK-transduced EPCs and EPCs after administration inhibitor cyclo to block the pathway of αvβ3 for 24 h, respectively. Upper 2 photos show Ad/hTK-transduced EPCs, lower 2 photos, EPCs (×100 magnification). B: Quantitative analysis of the cells migration, *P<0.05 between the Ad/hTK-transduced EPCs and non-transduced EPCs with the cyclo for 24 h.
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pone-0073035-g009: Inhibition of αvβ3 expression and the migration ability of EPCs.The inhibition of αvβ3 expression can lower the migration ability of EPCs. A: Representative macroscopic photographs of Ad/hTK-transduced EPCs and EPCs after administration inhibitor cyclo to block the pathway of αvβ3 for 24 h, respectively. Upper 2 photos show Ad/hTK-transduced EPCs, lower 2 photos, EPCs (×100 magnification). B: Quantitative analysis of the cells migration, *P<0.05 between the Ad/hTK-transduced EPCs and non-transduced EPCs with the cyclo for 24 h.

Mentions: This study examined whether the inhibition of integrin αvβ3 could lower the proliferation, migration, and adhesion abilities of EPCs. When EPCs were pretreated with 200 ug/ml of cyclo for 24 h, the number of EPCs that migrated strikingly decreased (EPCs: 77.90±7.23 versus 57.10±7.95, P<0.01; Ad/hTK-transduced EPCs: 99.60±7.10 versus 73.90±6.10, P<0.01) (Fig. 9).The number of adherent EPCs also decreased (EPCs: 186.00±6.90 versus 176.90±5.70, P<0.05; Ad/hTK-transduced EPCs: 194.30±8.20 versus 186.90±7.00, P<0.05) (Fig. 10). However, the proliferation presented no significant difference between the Ad/hTK-transduced EPCs and the non-transduced EPCs.


Kallikrein gene-modified EPCs induce angiogenesis in rats with ischemic hindlimb and correlate with integrin αvβ3 expression.

Fu SS, Li FJ, Wang YY, You AB, Qie YL, Meng X, Li JR, Li BC, Zhang Y, Da Li Q - PLoS ONE (2013)

Inhibition of αvβ3 expression and the migration ability of EPCs.The inhibition of αvβ3 expression can lower the migration ability of EPCs. A: Representative macroscopic photographs of Ad/hTK-transduced EPCs and EPCs after administration inhibitor cyclo to block the pathway of αvβ3 for 24 h, respectively. Upper 2 photos show Ad/hTK-transduced EPCs, lower 2 photos, EPCs (×100 magnification). B: Quantitative analysis of the cells migration, *P<0.05 between the Ad/hTK-transduced EPCs and non-transduced EPCs with the cyclo for 24 h.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3760867&req=5

pone-0073035-g009: Inhibition of αvβ3 expression and the migration ability of EPCs.The inhibition of αvβ3 expression can lower the migration ability of EPCs. A: Representative macroscopic photographs of Ad/hTK-transduced EPCs and EPCs after administration inhibitor cyclo to block the pathway of αvβ3 for 24 h, respectively. Upper 2 photos show Ad/hTK-transduced EPCs, lower 2 photos, EPCs (×100 magnification). B: Quantitative analysis of the cells migration, *P<0.05 between the Ad/hTK-transduced EPCs and non-transduced EPCs with the cyclo for 24 h.
Mentions: This study examined whether the inhibition of integrin αvβ3 could lower the proliferation, migration, and adhesion abilities of EPCs. When EPCs were pretreated with 200 ug/ml of cyclo for 24 h, the number of EPCs that migrated strikingly decreased (EPCs: 77.90±7.23 versus 57.10±7.95, P<0.01; Ad/hTK-transduced EPCs: 99.60±7.10 versus 73.90±6.10, P<0.01) (Fig. 9).The number of adherent EPCs also decreased (EPCs: 186.00±6.90 versus 176.90±5.70, P<0.05; Ad/hTK-transduced EPCs: 194.30±8.20 versus 186.90±7.00, P<0.05) (Fig. 10). However, the proliferation presented no significant difference between the Ad/hTK-transduced EPCs and the non-transduced EPCs.

Bottom Line: Expressions of integrin αvβ3 and endothelial nitric oxide synthase (eNOS) were detected on the surface of EPCs.The levels of integrin αvβ3 expression were reduced by PI3K and eNOS blockade, and the inhibitor of integrin αvβ3 abrogated the migration and adhesion of hTK-transduced EPCs (P<0.05). hTK gene delivery in vivo improves the natural angiogenic response to ischemia.The ability of hTK gene-transduced EPCs can be enhanced in vitro, in which integrin αvβ3 plays a role in the process.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.

ABSTRACT

Background: Human tissue kallikrein (hTK) plays an essential role in the physiological and pathological mechanisms of blood vessels. This study aimed to determine whether angiogenesis induced by endothelial progenitor cells (EPCs) transduced with the adenovirus-mediated hTK gene could improve blood flow in rat hindlimb ischemia in vivo and to establish a promising mechanism in vitro.

Methods: EPCs transduced with adenovirus encoding hTK-162 (i.e., Ad/hTK-transduced EPCs or Ad/GFP-transduced EPCs) were administered to Wister rats with hindlimb ischemia through therapeutic neovascularization. Muscular capillary density (MCD), blood flow (BF), and the number of myofibers were measured at days 7, 14, and 21 after treatment. Expressions of integrin αvβ3 and endothelial nitric oxide synthase (eNOS) were detected on the surface of EPCs.

Results: MCD, BF, and the number of myofibers in rats with Ad/hTK-transduced EPCs remarkably increased at day 21 after treatment compared with rats with Ad/GFP-transduced EPCs or the control group (P<0.01). Expressions of integrin αvβ3 and eNOS protein on the surface of EPCs also increased in rats with Ad/hTK-transduced EPCs. The levels of integrin αvβ3 expression were reduced by PI3K and eNOS blockade, and the inhibitor of integrin αvβ3 abrogated the migration and adhesion of hTK-transduced EPCs (P<0.05).

Conclusion: hTK gene delivery in vivo improves the natural angiogenic response to ischemia. The ability of hTK gene-transduced EPCs can be enhanced in vitro, in which integrin αvβ3 plays a role in the process.

Show MeSH
Related in: MedlinePlus