Limb ischemia after iliac ligation in aged mice stimulates angiogenesis without arteriogenesis

Tormod S. Westvik, Tamara N. Fitzgerald, Akihito Muto, Stephen P. Maloney, Jose M. Pimiento, Tiffany T. Fancher, Dania Magri, Hilde H. Westvik, Toshiya Nishibe, Omaida C Velazquez, Alan Dardik

Research output: Contribution to journalArticle

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Abstract

Objective: Older patients are thought to tolerate acute ischemia more poorly than younger patients. Since aging may depress both angiogenesis and arteriogenesis, we determined the effects of age on both angiogenesis and arteriogenesis in a model of severe acute limb ischemia. Methods: Young adult (3-months-old) and aged (18-months-old) C57BL/6 mice underwent right common iliac artery and vein ligation and transection. Data were collected on days 0, 7, and 14. Perfusion was measured with a laser Doppler scan and compared to the contralateral limb. Functional deficits were evaluated with the Tarlov scale. Capillary density and endothelial progenitor cell (EPC) number were determined by direct counting lectin-positive/alpha-actin-negative cells and VEGFR2/CXCR4 dually-positive cells, respectively; angiography was performed to directly assess arteriogenesis. Results: Young adult and aged mice had a similar degree of decreased perfusion after iliac ligation (young, n = 15: 20.4 ± 1.9%, vs aged, n = 20: 19.6 ± 1.3%; P = .72, analysis of variance [ANOVA]); however, young mice recovered faster and to a greater degree than aged mice (day 7, 35 ± 6% vs 17 ± 4%, P = .046; day 14, 60 ± 5% vs 27 ± 7%, P = .0014). Aged mice had worse functional recovery by day 14 compared to young mice (2.3 ± 0.3 vs 4.3 ± 0.4; P = .0021). Aged mice had increased capillary density (day 7, 12.9 ± 4.4 vs 2.8 ± 0.3 capillaries/hpf; P = .02) and increased number of EPC incorporated into the ischemic muscle (day 7, 8.1 ± 0.9 vs 2.5 ± 1.9 cells; P = .007) compared to young mice, but diminished numbers of collateral vessels to the ischemic limb (1 vs 9; P = .01), as seen on angiography. Conclusion: After severe hind limb ischemia, aged animals become ischemic to a similar degree as young animals, but aged animals have significantly impaired arteriogenesis and functional recovery compared to younger animals. These results suggest that strategies to stimulate arteriogenesis may complement those that increase angiogenesis, and may result in improved relief of ischemia.

Original languageEnglish
Pages (from-to)464-473
Number of pages10
JournalJournal of Vascular Surgery
Volume49
Issue number2
DOIs
StatePublished - Feb 1 2009

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Ligation
Ischemia
Extremities
Young Adult
Angiography
Perfusion
Iliac Vein
Iliac Artery
Inbred C57BL Mouse
Lectins
Actins
Analysis of Variance
Lasers
Cell Count
Muscles

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery

Cite this

Westvik, T. S., Fitzgerald, T. N., Muto, A., Maloney, S. P., Pimiento, J. M., Fancher, T. T., ... Dardik, A. (2009). Limb ischemia after iliac ligation in aged mice stimulates angiogenesis without arteriogenesis. Journal of Vascular Surgery, 49(2), 464-473. https://doi.org/10.1016/j.jvs.2008.08.077

Limb ischemia after iliac ligation in aged mice stimulates angiogenesis without arteriogenesis. / Westvik, Tormod S.; Fitzgerald, Tamara N.; Muto, Akihito; Maloney, Stephen P.; Pimiento, Jose M.; Fancher, Tiffany T.; Magri, Dania; Westvik, Hilde H.; Nishibe, Toshiya; Velazquez, Omaida C; Dardik, Alan.

In: Journal of Vascular Surgery, Vol. 49, No. 2, 01.02.2009, p. 464-473.

Research output: Contribution to journalArticle

Westvik, TS, Fitzgerald, TN, Muto, A, Maloney, SP, Pimiento, JM, Fancher, TT, Magri, D, Westvik, HH, Nishibe, T, Velazquez, OC & Dardik, A 2009, 'Limb ischemia after iliac ligation in aged mice stimulates angiogenesis without arteriogenesis', Journal of Vascular Surgery, vol. 49, no. 2, pp. 464-473. https://doi.org/10.1016/j.jvs.2008.08.077
Westvik TS, Fitzgerald TN, Muto A, Maloney SP, Pimiento JM, Fancher TT et al. Limb ischemia after iliac ligation in aged mice stimulates angiogenesis without arteriogenesis. Journal of Vascular Surgery. 2009 Feb 1;49(2):464-473. https://doi.org/10.1016/j.jvs.2008.08.077
Westvik, Tormod S. ; Fitzgerald, Tamara N. ; Muto, Akihito ; Maloney, Stephen P. ; Pimiento, Jose M. ; Fancher, Tiffany T. ; Magri, Dania ; Westvik, Hilde H. ; Nishibe, Toshiya ; Velazquez, Omaida C ; Dardik, Alan. / Limb ischemia after iliac ligation in aged mice stimulates angiogenesis without arteriogenesis. In: Journal of Vascular Surgery. 2009 ; Vol. 49, No. 2. pp. 464-473.
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AU - Westvik, Tormod S.

AU - Fitzgerald, Tamara N.

AU - Muto, Akihito

AU - Maloney, Stephen P.

AU - Pimiento, Jose M.

AU - Fancher, Tiffany T.

AU - Magri, Dania

AU - Westvik, Hilde H.

AU - Nishibe, Toshiya

AU - Velazquez, Omaida C

AU - Dardik, Alan

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N2 - Objective: Older patients are thought to tolerate acute ischemia more poorly than younger patients. Since aging may depress both angiogenesis and arteriogenesis, we determined the effects of age on both angiogenesis and arteriogenesis in a model of severe acute limb ischemia. Methods: Young adult (3-months-old) and aged (18-months-old) C57BL/6 mice underwent right common iliac artery and vein ligation and transection. Data were collected on days 0, 7, and 14. Perfusion was measured with a laser Doppler scan and compared to the contralateral limb. Functional deficits were evaluated with the Tarlov scale. Capillary density and endothelial progenitor cell (EPC) number were determined by direct counting lectin-positive/alpha-actin-negative cells and VEGFR2/CXCR4 dually-positive cells, respectively; angiography was performed to directly assess arteriogenesis. Results: Young adult and aged mice had a similar degree of decreased perfusion after iliac ligation (young, n = 15: 20.4 ± 1.9%, vs aged, n = 20: 19.6 ± 1.3%; P = .72, analysis of variance [ANOVA]); however, young mice recovered faster and to a greater degree than aged mice (day 7, 35 ± 6% vs 17 ± 4%, P = .046; day 14, 60 ± 5% vs 27 ± 7%, P = .0014). Aged mice had worse functional recovery by day 14 compared to young mice (2.3 ± 0.3 vs 4.3 ± 0.4; P = .0021). Aged mice had increased capillary density (day 7, 12.9 ± 4.4 vs 2.8 ± 0.3 capillaries/hpf; P = .02) and increased number of EPC incorporated into the ischemic muscle (day 7, 8.1 ± 0.9 vs 2.5 ± 1.9 cells; P = .007) compared to young mice, but diminished numbers of collateral vessels to the ischemic limb (1 vs 9; P = .01), as seen on angiography. Conclusion: After severe hind limb ischemia, aged animals become ischemic to a similar degree as young animals, but aged animals have significantly impaired arteriogenesis and functional recovery compared to younger animals. These results suggest that strategies to stimulate arteriogenesis may complement those that increase angiogenesis, and may result in improved relief of ischemia.

AB - Objective: Older patients are thought to tolerate acute ischemia more poorly than younger patients. Since aging may depress both angiogenesis and arteriogenesis, we determined the effects of age on both angiogenesis and arteriogenesis in a model of severe acute limb ischemia. Methods: Young adult (3-months-old) and aged (18-months-old) C57BL/6 mice underwent right common iliac artery and vein ligation and transection. Data were collected on days 0, 7, and 14. Perfusion was measured with a laser Doppler scan and compared to the contralateral limb. Functional deficits were evaluated with the Tarlov scale. Capillary density and endothelial progenitor cell (EPC) number were determined by direct counting lectin-positive/alpha-actin-negative cells and VEGFR2/CXCR4 dually-positive cells, respectively; angiography was performed to directly assess arteriogenesis. Results: Young adult and aged mice had a similar degree of decreased perfusion after iliac ligation (young, n = 15: 20.4 ± 1.9%, vs aged, n = 20: 19.6 ± 1.3%; P = .72, analysis of variance [ANOVA]); however, young mice recovered faster and to a greater degree than aged mice (day 7, 35 ± 6% vs 17 ± 4%, P = .046; day 14, 60 ± 5% vs 27 ± 7%, P = .0014). Aged mice had worse functional recovery by day 14 compared to young mice (2.3 ± 0.3 vs 4.3 ± 0.4; P = .0021). Aged mice had increased capillary density (day 7, 12.9 ± 4.4 vs 2.8 ± 0.3 capillaries/hpf; P = .02) and increased number of EPC incorporated into the ischemic muscle (day 7, 8.1 ± 0.9 vs 2.5 ± 1.9 cells; P = .007) compared to young mice, but diminished numbers of collateral vessels to the ischemic limb (1 vs 9; P = .01), as seen on angiography. Conclusion: After severe hind limb ischemia, aged animals become ischemic to a similar degree as young animals, but aged animals have significantly impaired arteriogenesis and functional recovery compared to younger animals. These results suggest that strategies to stimulate arteriogenesis may complement those that increase angiogenesis, and may result in improved relief of ischemia.

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