TY - JOUR
T1 - Retention of endothelial progenitor cells in bone marrow in a murine model of endogenous tissue plasminogen activator (tPA) deficiency in response to critical limb ischemia
AU - Leu, Steve
AU - Lu, Hung I.
AU - Sun, Cheuk Kwan
AU - Sheu, Jiunn Jye
AU - Chen, Yung Lung
AU - Tsai, Tzu Hsien
AU - Yeh, Kuo Ho
AU - Chai, Han Tan
AU - Chua, Sarah
AU - Tsai, Ching Yen
AU - Chang, Hsueh Wen
AU - Lee, Fan Yen
AU - Yip, Hon Kan
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Background This study tested the hypothesis that tissue plasminogen activator (tPA) is crucial for regulating endothelial progenitor cell (EPC) mobilization from bone marrow to circulation in murine critical limb ischemia (CLI) by ligating the left femoral artery. Methods Wild-type (C57BL/6) (n = 40) mice were equally divided into group 1A (sham control), group 2A (CLI), group 3A [control-tPA (4.0 mg/kg)] and group 4A [CLI-tPA (intravenously at 3 h after CLI)]. Similarly, tPA knock-out (tPA-/-) mice (n = 40) were equally divided into group 1B (sham control), group 2B (CLI), group 3B [control-tPA (4.0 mg/kg)], and group 4B (CLI-tPA). Results The circulating levels of EPCs (C-kit/CD31 +, Sca-1/KDR +, CXCR4/CD34 +) were lower in groups 1B and 2B than in groups 1A and 2A, respectively (all p < 0.01), and were reversed after tPA treatment (3B vs. 3A or 4B vs. 4A, p > 0.05) at 6 h and 18 h post-CLI. Levels of these biomarkers decreased again 14 days after CLI in tPA-/- mice compared to those in wild-type between the respective groups (all p < 0.01). Laser Doppler flowmetry showed a higher ratio of ischemic-to-normal blood flow in 2A than in 2B and in 4A than in 4B by day 14 after CLI (all p < 0.05). Angiogenesis at protein (CXCR4, SDF-1α, VEGF) and cellular (CXCR4 +, SDF-1α +, and CD31 + cells) levels was highest in animals with CLI-tPA, significantly higher in mice with CLI only than in sham controls for both wild-type and tPA-/- mice (p < 0.01). Conclusion tPA played an essential role in augmenting circulating EPCs, angiogenesis, and blood flow in the ischemic limb in a murine model.
AB - Background This study tested the hypothesis that tissue plasminogen activator (tPA) is crucial for regulating endothelial progenitor cell (EPC) mobilization from bone marrow to circulation in murine critical limb ischemia (CLI) by ligating the left femoral artery. Methods Wild-type (C57BL/6) (n = 40) mice were equally divided into group 1A (sham control), group 2A (CLI), group 3A [control-tPA (4.0 mg/kg)] and group 4A [CLI-tPA (intravenously at 3 h after CLI)]. Similarly, tPA knock-out (tPA-/-) mice (n = 40) were equally divided into group 1B (sham control), group 2B (CLI), group 3B [control-tPA (4.0 mg/kg)], and group 4B (CLI-tPA). Results The circulating levels of EPCs (C-kit/CD31 +, Sca-1/KDR +, CXCR4/CD34 +) were lower in groups 1B and 2B than in groups 1A and 2A, respectively (all p < 0.01), and were reversed after tPA treatment (3B vs. 3A or 4B vs. 4A, p > 0.05) at 6 h and 18 h post-CLI. Levels of these biomarkers decreased again 14 days after CLI in tPA-/- mice compared to those in wild-type between the respective groups (all p < 0.01). Laser Doppler flowmetry showed a higher ratio of ischemic-to-normal blood flow in 2A than in 2B and in 4A than in 4B by day 14 after CLI (all p < 0.05). Angiogenesis at protein (CXCR4, SDF-1α, VEGF) and cellular (CXCR4 +, SDF-1α +, and CD31 + cells) levels was highest in animals with CLI-tPA, significantly higher in mice with CLI only than in sham controls for both wild-type and tPA-/- mice (p < 0.01). Conclusion tPA played an essential role in augmenting circulating EPCs, angiogenesis, and blood flow in the ischemic limb in a murine model.
KW - Critical limb ischemia
KW - Endothelial progenitor cells
KW - Knockout mice model
KW - Tissue plasminogen activator
UR - http://www.scopus.com/inward/record.url?scp=84890971699&partnerID=8YFLogxK
U2 - 10.1016/j.ijcard.2013.11.021
DO - 10.1016/j.ijcard.2013.11.021
M3 - 文章
C2 - 24290069
AN - SCOPUS:84890971699
SN - 0167-5273
VL - 170
SP - 394
EP - 405
JO - International Journal of Cardiology
JF - International Journal of Cardiology
IS - 3
ER -